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PHYSIOLOGYNEWS
spring 2005 | number 58
IUPS 2005
Images of the Bristol, Nottingham, Oxford and KCL
Meetings
Also featuring:
Living history – the case of the misbehaving circuit
50 years of caveolae
Obesity – why all the noise?
From tadpole to frog: a tale of two networks
The Nobel Prize
A publication of the Physiological Society
King’s College London
Images from and around
King’s College London,
venue for the Physiological
Society Meeting
17-20 December, 2004
(photos by Prem Kumar)
More images from the KCL Meeting
appear on the inside back cover
PHYSIOLOGYNEWS
Editorial 3
IUPS 2005 4
Images of KCL Prem Kumar, David Eisner ifc, ibc
The Society’s dog. ‘Rudolf Magnus gave Oxford Focused Meeting Denis Noble 5
me to Charles Sherrington, who gave me Nottingham Focused Meeting Paul Greenhaff 6
to Henry Dale, who gave me to the Bristol Focused Meeting Sergey Kasparov, Julian Paton 7
Physiological Society in October 1942’ ‘The Senses’ Karl Gegenfurtner 8
Living History
The case of the misbehaving circuit Stanley Salmons 9
Published quarterly by the Physiological Society
A summer in the life of ... Giovanni Mann 11
Contributions and Queries
Executive Editor Features
Linda Rimmer The Nobel Prize Tim Jacob 12
The Physiological Society 50 years of caveolae - a round-up Michael Taggart 13
Publications Office
Obesity - why all the noise? Paul Trayhurn 15
Building 4A, The Michael Young Centre
Metamorphosis from tadpole to frog: a tale of two networks Denis
Purbeck Road
Cambridge CB2 2HP
Combes, Simon Merrywest, John Simmers, Keith Sillar 17
Impact of the intrauterine environment on respiratory health throughout
Tel: +44 (0)1223 400180 life Richard Harding, Megan Cock, Gert Maritz 19
Fax: +44 (0)1223 246858 The interdependence of cell volume and resting membrane potential
Email: lrimmer@physoc.org James Fraser, Christopher L-H Huang 21
The Society web server: http://www.physoc.org Mechanosensory transduction in the enteric nervous system Terence
Smith, Nick Spencer, Grant Hennig 23
Magazine Editorial Board The fire within: fuel selection in shivering muscles François Haman,
Editor Stéphane Legault, Jean-Michel Weber 26
Austin Elliott (University of Manchester) Differential screening of a subtractive cDNA library reveals that maternal
Members undernutrition affects fetal heart gene expression Hyungchul Han,
Lesley Anson (Nature) Thomas Hansen 28
Laura Blackburn (University of Cambridge) NMDA receptor kinetics are tuned for coincidence detection during
Munir Hussain (University of Liverpool) spike-timing dependent synaptic plasticity Björn Kampa, Greg Stuart 29
John Lee (Rotherham General Hospital) Myocardial connexin 43: gap junction-dependent and gap junction
Thelma Lovick (University of Birmingham) independent effects on ischaemia/reperfusion injury Antonio Rodriguez-
Bill Winlow (Prime Medica, Knutsford) Sinovas, David Garcia-Dorado, Alberto Cabestrero, Marisol Ruiz-Meana 31
Endocrine granules David Perrais, Justin Taraska, Wolfhard Almers 33
© 2005 The Physiological Society Exploring connections between the cerebellum and motor cortex in
ISSN 1476-7996 humans Jeff Daskalakis, Robert Chen 35
Bilateral interactions between the upper limbs Richard Carson,
The Society permits the single copying of Stephan Riek, Winston Byblow 37
individual articles for private study or research. For Fishing for 02 chemoreceptors in vertebrates Michael Jonz,
copying or reproduction for any other purpose, Colin Nurse 39
written permission must be sought from the
Physiological Society (lrimmer@physoc.org). International News
Transport mechanisms across cell membranes David Brown,
Opinions expressed in articles and letters submitted
Myrtani Pieri 41
by, or commissioned from, Members, Affiliates or
outside bodies are not necessarily those of the
Physiological Society.
Affiliate News
When is a young physiologists’ symposium NOT a young physiologists’
The Physiological Society is registered in England symposium? Charlotte Waters 43
as a company limited by guarantee: No 323575.
Registered office: PO Box 11319, London WC1X
8WQ The Dead Ringer team clean up at
Registered Charity: No 211585. Lastingham Dead Ringer Society 44
Printed by The Lavenham Press Ltd Letters to the Editor 45
Society News
Cover photo New Council members Austin Elliott 34
Cover illustration from Combes et al. p. 17
Profiting from Postgraduate Talent 2004 Sarah Blackford 46
Ventral view of metamorphosing
stage 61 Xenopus tadpole. G L Brown Lecture Judy Harris, Michael Rennie 47
Background activity is rhythmic Benevolent Fund Joanna Rattray 48
spinal ventral root discharge Deceased Members 48
simultaneously driving tail Where does my future lie? Sai Pathmanathan 48
oscillations during swimming (top Biology in the real world Sai Pathmanathan 48
trace) and limb extension-flexion
thrusts (lower traces). What have Council been talking about? Austin Elliott 49
Photography courtesy of Sean
Earnshaw, University of St Andrews, Funding boost for graduate training in
using a Nikon FM SLR camera with animal research Clare Stanford 40
110 mm macro lens. Unbelievable! 50
Book Reviews 50
Noticeboard 18
PHYSIOLOGYNEWS
Action points Guidelines for contributors
Grants These guidelines are intended to assist
In this issue
This issue of Physiology News contains
For full information on Members’ authors in writing their contributions and to
several examples of the serendipity on which
and Affiliates’ Grants, Pfizer in vivo reduce the subsequent editing process. The
science often depends. A trained mind asking
Physiology Grants, Network Editorial Group of Physiology News tries to the right questions is essential in research,
Interaction Grants, Non-Society ensure that all articles are written in a but serendipity and chance play a role too. A
journalistic style so that they will have an thought in the right place; a totally
Symposia Grants, Postgraduate
immediate interest value for a wide unexpected observation; a chance finding
Support Fund information and the readership and will be readable and that leads somewhere unforeseen.
Vacation Studentship Scheme visit: comprehensible to non-experts. In
http://www.physoc.org/grants particular, scientific articles should give a For me personally this is a big part of the
good overview of a field rather than focus attraction of doing research, and also part of
Membership applications entirely on the authors’ own research. what makes research and its history
interesting to read about. In Living History,
Applications for Full and Affiliate Stanley Salmons gives an example of
Membership are received throughout Format of articles
The main message or question posed should be serendipity when he describes how a simple
the year and have no deadlines. A introduced in the first paragraph. The background malfunctioning circuit took him down many
decision is normally made within 8 for the topic should then be established, leading new scientific avenues, and even into cardiac
10 weeks of the Administration up to the final conclusion. surgery.
Office receiving the application. For
Length of articles Sometimes, of course, it can take a long time
full details please visit: This will be determined by the subject matter and for a serendipitous finding to be fully
http://www.physoc.org/join agreed with the Editorial Administrator. appreciated. As Mike Taggart describes on
p. 13, it has taken caveolae 50 years, but
Submission of articles they definitely seem to have made it from
Change of address Authors should submit articles as a Word morphological curiosity to centre stage in
Members should inform the document attached to an email. Illustrations cell biology.
Administration Office of any changes should be sent as separate attachments (see below)
of address, telephone, fax or email and not embedded in the text.
Another of the charms of research is that
address. Illustrations and authors’ photographs
nothing is ever set in stone. Paradigms
change, and even in the best-explored areas
Changes can be emailed to: Authors are encouraged to submit diagrams,
there are new ideas to be found, and new
jgould@physoc.org or updated online drawings, photographs or other artwork with their
articles or to suggest appropriate illustrations. A ways of looking at things, as Fraser and
at http://www.physoc.org photograph of the author(s) should also Huang explore for the GHK equation (p. 21).
accompany submissions, if possible. Illustrations
and photographs may be colour or black and Aside from those brief highlights, we have a
white, prints, transparencies or tif/jpeg files with a full issue's worth of science News and
minimum resolution of 300 dpi. Electronic Views, Features, and Society news. We
Physiology News colour figures should be saved in CMYK mode. preview some IUPS and San Diego
attractions, introduce you to your new
Deadlines References Council members on p. 34 and highlight
Authors are requested to keep the number of what the Council has been talking about on
Letters and articles and all other references to a minimum – preferably no more p. 49. Plus the joys (?) of research
contributions for inclusion in the than two or three. Please cite all references in the committees and themes in Unbelievable!
Summer 2005 issue, No. 59, should style of The Journal of Physiology (see Happy Easter.
reach the Publications Office Instructions to Authors 2005 at
http://www.physoc.org) Austin Elliott
(lrimmer@physoc.org) by 20 April,
2005. Short news items are
encouraged and can usually be
included as late copy if space
permits.
Suggestions for articles
Suggestions for future articles are
welcome. Please contact either the
Editorial Administrator or a member
of the Editorial Group of Physiology
News (see contents page for details).
Physiology News Online
Physiology News is now available on
our website: http://www.physoc.org.
EDITORIAL PN 3
Democracy? Ho hum NB to Council: could be time to
triple the membership charges.
Society’s parliament, it was felt,
directly elected by the membership
At its 2004 Annual General Meeting and therefore accountable to them.
in Cork, the Members of the Note, though, that there was more In addition, really significant
Physiological Society voted to on the relevant voting paper than changes in how the Society’s rules
abolish voting on oral just the changes in voting on were drawn would require a vote of
communications and posters. communications. There were also the Members. A referendum, in
some changes in the make-up of the effect.
Well, I say ‘the Members’. I could group of Trustees who are legally
(more accurately) have said ‘well responsible for running the Society Unfortunately, aspects of this don’t
under 5% of the Members’. (Physiology News, 57, 41). So on seem to be working.
the above reasoning we would have
No precise numbers – the to conclude that the Members Perhaps an incentive is needed.
scrutineers winced at the prospect wanted those to go through too. Maybe the Society should offer a £5
of them being repeated here, and discount off the annual membership
had a lapse of memory. Or that we don’t care. Take your fee to people who actually send
pick. back their ballot papers.
Given the 100-plus years that the
Society’s tradition of voting on One thing this is not, though, is NB to Council: how about this: put
communications had existed, it fully-functional Society democracy. the annual membership fee up £10,
might seem pretty surprising that so Misfunctioning, or even and then offer £5 off if they vote.
few of the Society’s Members could dysfunctional, maybe.
rouse themselves to vote. Whatever the Society decides to do
To repeat: it is only functioning if (or doesn’t decide, or decides not to
One rather expects that few people we – the Members – all are 100% do) about this, there is one point
will trudge along to AGMs, whether happy that our not voting means we that cannot be reiterated enough.
for Trades Unions, learned Societies don’t care what the result is.
or residents associations. Unless In a democracy, people get to think
they are, respectively, trying to stop As I have written before, I find this for themselves. But if what they
your university being closed, trying hard to believe, given what an think is that they’re not bothered,
to triple your membership charges, argumentative bunch physiologists then they can have no complaints if
or opposing the construction of a are. In my experience most they don’t like what gets done in
railway line at the end of your scientists prefer to spend their free their name.
garden. time, like their lunch hours,
debating, arguing, grumbling and, ‘Well I didn’t vote for any of them,
But less than 5% of the Society’s occasionally, eating. Put half a so you can’t blame me.’
Members could even be bothered to dozen of them in a bar during a
vote via a postal ballot that had Society Meeting, start an argument Wrong.
been mailed out to them. about whether voting on
There is an apt quote for this sort of
communications is a waste of time,
Reading something, ticking a few ailing democratic-but-participation
and watch them go.
boxes, and stuffing the piece of light process, usually attributed to
paper in an envelope. How difficult So what makes us so vote-shy? the American politician Adlai
or time-consuming is that? Stevenson:
The major changes in Governance
If one is being charitable, one can at the Society a few years ago, in ‘In a democracy, people get the
read the (lack of) response of the particular the change to a fully government they deserve.’
membership as being a tacit elected Council, were a laudable
approval of the change. People Remember that when you get this
attempt to make the Society more
probably see that the motion is year’s voting papers.
democratic and give the Members
being proposed by the Society’s more of a direct say in how the Austin Elliott
Council, assume it will go through, Society was run. The Society’s
and approve by doing nothing. Council should be a bit like the
Physiology News | No. 58 | Spring 2005 | www.physoc.org
4 PN IUPS
IUPS 2005
As a decent number of Physiological Society Members troop off to the IUPS meeting in San
Diego, we preview some of the attractions…
First - the meeting! Grant. Don’t blame us if you get
… of course, the biggest attraction is arrested, though.
the IUPS conference itself. After all,
what could be more enticing than the • Visit Sea World; entrance is a slightly
prospect of meeting up with 2000+ painful $50, but the Killer Whale show
other bioscientists from all around the is quite something (word of warning;
world? Well, the prospect of meeting wear something waterproof if you are
up with 2000+ scientists somewhere going to sit in one of the first 10 rows).
sunny. IUPS conferences have a long For a preview visit the webcam at:
and distinguished history – this one is http://www.shamu.com/ca/shamu
the 35th, with the first having taken cam/index.htm
place in Basel in 1889 - and have
visited many locations around the • For the young (or at least young-at
world, but sunshine and an exotic heart), wander down to Pacific Beach
location is always a plus. The last three (‘PB’) to take in the nightlife. Don’t
meetings, for those that weren’t there, forget to rehydrate afterwards.
were a slightly damp and chilly Alternatively, go there in the day to
Glasgow in 1993 (the last time the stroll along the beach. For a ‘Surfcam’
IUPS came to Britain), St Petersburg in preview and other local surf info have a
1997 (described by participants as look at: http://scilib.ucsd.edu/sio/ocean/
‘unforgettable’, for a whole range of
reasons) and most recently • Visit Balboa Park for a day to do the
Christchurch in 2001. For anyone museums (multi-museum day tickets
interested, a report on this last meeting available for around $30), go to the
can still be found on our website in zoo, or just stroll around. NB: Some bus
issue 45 (Winter 2001). routes from the hotel district to Balboa
Park do go through ‘interesting’ parts
Second, the city of town; watch out for bus-stop benches
San Diego has many visitor attractions, with signs like: ‘In jail? Make bail! –
and as a small service we have call 1-800-BOND-OUT’
provided a brief list of must
visits/must-dos (purely for those who From the top: • Take the coast light railway - the
have spare days, of course). Physiology News Editor Austin Elliott visits the Hotel ‘San Diego trolley’ - down to Tijuana
del Coronado; life’s a beach in San Diego; beware of and stroll over into Mexico for duty
killer whales at Sea World.
free shopping, Mexican food, and
IUPS 2005 ‘other attractions’.
th You should…
35 Congress of the International Union
of Physiological Sciences • Have dinner on a restaurant terrace Want to try your hand as a
San Diego, CA, USA overlooking the ocean (or at least writer?
within earshot of the sea) in La Jolla Due to scheduling conflicts none of the
31 March – 5 April, 2005
regular Physiology News team will be
(http://www.IUPS2005.org) • Have lunch at the famous Hotel del reporting from the IUPS. We would
Coronado (The ‘Del’) on Coronado therefore welcome brief reports (300
Two Journal of Physiology symposia will take place
Island. The ‘Del’ is where the future words) on the meeting from anyone who
at the IUPS:
Edward VIII of England first met Mrs would like a shot at being a stand-in
PDZ domain scaffolding proteins and their Simpson, and will also be immediately Conference/Foreign Correspondent, and
functions in polarized cells (4 April) recognisable to anyone who has seen thinks they could be both entertaining
TRP channels: physiological genomics and the movie Some Like It Hot. True and informative. We will pay £50 for
proteomics (5 April) movie buffs can buy a blue blazer and any pieces published and are keen to get
yachting cap at one of San Diego’s views from physiologists of all ages - so
first-rate thrift stores and try pretending come on, get your reporter’s notebook
(http://www.jphysiol.org)
to be Tony Curtis pretending to be Cary out.
Physiology News | No. 58 | Spring 2005 | www.physoc.org
OXFORD FOCUSED MEETING PN 5
Oxford Focused Meeting calcium transients and calcium
handling was published instead by The
that. The irony is obvious. The
significance lies much deeper and is
The Society’s first meeting Royal Society (DiFrancesco & Noble, more important. As Hodgkin and
on modelling in physiology 1985). I believe that was also the point Huxley’s work showed: the best
at which the traditional ‘British’ simulation work in physiology is
I built my first cardiac cell model in approach to the life science started to strongly based experimentally, and it
1960 (Noble, 1960) following the lose ground to the more pragmatic style succeeds to the extent that it interacts
discovery of the potassium channels, iK1 championed in the United States, where further with experimental work, both by
and iK, in cardiac Purkinje fibres Bioengineering groups at various suggesting new experiments and by
(Hutter & Noble, 1960). In October universities took up the challenge, itself developing in iterative interaction
2004, the Society held its first ever including notably the work of Luo and with them.
meeting devoted to modelling in Rudy (1994) and of Raimond Winslow
physiology. There can’t be many other (Rice et al. 1999). The preferred key This strategy can also be linked to the
areas of our science that have waited 44 journals now include the American growing popularity of what has come to
years for a dedicated meeting! One Journal of Physiology (where my latest be called ‘systems biology’. No-one is
could argue that it is 52 years, since the modelling work has been published), quite sure what the term means, but
paradigm model was that of Hodgkin the Journal of General Physiology, physiologists can be clear that, at the
and Huxley (Hodgkin & Huxley, 1952). Circulation Research and the least, it includes quantitative analysis of
It was therefore a great pleasure to be Biophysical Journal. These are all the areas that are traditionally called
able to welcome Sir Andrew Huxley to published in the USA. It is worth systems physiology. It also includes
introduce the Hodgkin-Huxley-Katz noting, though, that Philosophical what molecular and genomic biologists
lecture on the first day of the meeting. Transactions of the Royal Society and now refer to as the theory of
Progress in Biophysics and Molecular interactions. The distinguished
Why such a long delay? One reason is Biology continue to be active in this geneticist Gabriel Dover (2000) goes
that, until fairly recently, the Society area. as far as to say: ‘We don’t have a
has not held focused meetings on any theory of interactions and until we do
subject. When I started work as In fact, we now find ourselves having we cannot have a theory of
Meetings Secretary in 1974 all the to catch up. The Oxford meeting was development or a theory of evolution’.
Society’s meetings were general. an excellent contribution to achieving This is therefore also the route by
Moreover, the Secretary was required that, since it showed how strong the which physiology can reconnect with
to mix all the topics up in each meeting field still is here in the UK, but it was the mainstream of biological thought,
by arranging the abstracts in the order also a strongly international one, with including developmental biology and
in which they were received. I was the presentations from countries as far evolutionary biology (Diamond, 1993).
first to break this tradition by flung as the USA, Japan, Russia,
Canada and New Zealand. There were Finally, I hope we don’t have to wait a
organising abstracts into sessions with
roughly equal numbers of talks further 44 years before the next Society
oral presentations on similar topics
presented from the UK and from meeting on modelling work (I might
forming each session. So, it is only
abroad. The meeting attracted 127 not be around to witness that!).
during the last 30 years that focused
sessions, and then complete focused participants, and was sponsored by the Denis Noble
meetings, have been held. British Heart Foundation, Pfizer and University of Oxford, UK
Novartis, as well as by the
Physiological Society. Philosophical References
But I think there is also a deeper,
Diamond JM. (1993). Evolutionary physiology. In The Logic of Life,
philosophical reason. British Transactions of the Royal Society will ed. Boyd CAR & Noble D, pp 89-111. OUP, Oxford.
physiology has been so keen on its be publishing around 30 papers in a
DiFrancesco D & Noble D (1985). A model of cardiac electrical
empirical tradition, reflected also in the volume arising from the meeting, while activity incorporating ionic pumps and concentration changes.
strength of empiricism in British the Hodgkin-Huxley-Katz lecture will Philosophical Transactions of the Royal Society B 307, 353-398.
philosophy, that it has been fairly be published in The Journal of Dover G (2000). Dear Mr Darwin. Letters on the evolution of life and
Physiology. human nature. Weidenfeld and Nicolson, London.
antipathetic to theoretical work. Notice,
in the title of Hodgkin and Huxley’s Hodgkin AL & Huxley AF (1952). A quantitative description of
membrane current and its application to conduction and excitation in
paper, that they refer to ‘a quantitative A second significant sign lies in the nerve. J Physiol 117, 500-544.
description’ rather than to ‘a strategy of the Journal of Experimental
Hutter OF & Noble D (1960). Rectifying properties of heart muscle.
quantitative theory’. Physiology, whose Editorial Board has Nature 188, 495.
announced that it wishes to foster
Luo C & Rudy Y (1994). A Dynamic model of the cardiac ventricular
Nevertheless, the early papers on nerve quantitative integrative physiology, action potential - simulations of ionic currents and concentration
and heart cell models were nearly all including modelling. A future focused changes. Circulation Research 74, 1071-1097.
published in The Journal of Physiology. volume will be devoted to this field. A Noble D (1960). Cardiac action and pacemaker potentials based on
journal of experimental physiology the Hodgkin-Huxley equations. Nature 188, 495-497.
That tradition was broken in 1985 when
the work that Dario DiFrancesco and I sponsoring theoretical work?! I like Rice JJ, Jafri MS & Winslow RL (1999). Modeling gain and
both the irony and the significance of gradedness of Ca2+ release in the functional unit of the cardiac
published on the first simulations of diadic space. Biophys J 77, 1871-1884.
Physiology News | No. 58 | Spring 2005 | www.physoc.org
6 PN NOTTINGHAM FOCUSED MEETING
Nottingham Focused
Meeting
Responsiveness of muscle,
bone and connective tissue
to physical activity: genetic
and molecular integration
The first Focused Meeting of the
Physiological Society took place at
the University of Nottingham
Graduate Entry Medical School in
Derby from 12-13 July, 2004
It’s clear that the application of modern
techniques in physiology is providing Over 60 delegates attending found the new Meeting format highly enjoyable and productive
us with unforeseen knowledge
concerning the way in which our linking of changes in muscle myo hosted by the Centre for Integrated
musculo-skeletal mass maintains itself filament turnover with the turnover of Systems Biology and Medicine
and adapts under both catabolic extra-cellular matrix, the marked (http://www.nottingham.ac.uk/cisbm/)
(immobilisation, space flight, response of tendon to exercise, the at the University of Nottingham. It
hospitalisation) and anabolic (growth in existence of genetic traits which make highlighted recent research addressing
childhood, strength training/body human beings good or poor responders the responsiveness of muscle, bone and
building, rehabilitation) conditions. to exercise, etc. connective tissue to physical activity,
Some remarkable physiological and in particular recent genetic and
phenomena have been discovered This, the first Focused Meeting of the molecular advances to our
recently, e.g. the marked anabolic Physiological Society, organised by understanding of what controls tissue
response of bone to vibration, the Paul Greenhaff and Mike Rennie, was mass under these conditions.
The 2 day event allowed contemporary
physiological findings to be set in a
context of transcriptional and
translational control of the tissues of
the musculo-skeletal system, some of
which like bone and tendon had
hitherto been thought only to respond
weakly and slowly. The meeting was
attended by over 60 delegates, and
lecture presentations by an international
panel of symposium speakers were
accompanied by original
communications by attendees.
The overwhelming opinion from
Members was that this new format of
Meeting was highly enjoyable and
productive, facilitating detailed
discussion in an informal and friendly
environment (particularly in the bar
following the symposium dinner).
Top left: .Marco Narici, Martin Thompson and Mike
Clearly this new initiative of the
White enjoying lunch (left to right) Society should go from strength to
Top right and centre: Delegates engrossed in informal strength… (please pardon the pun).
discussions
Left: Arnold de Haan, David Jones and Michael Paul Greenhaff
Rennie (left to right) debate the merits of the new School of Biomedical Sciences, University of
focused meeting format of the Society. Nottingham, UK
Physiology News | No. 58 | Spring 2005 | www.physoc.org
BRISTOL FOCUSED MEETING PN 7
The University of Bristol hosted this 2 (Institute of Bioengineering and
day meeting sponsored by the Nanotechnology, Singapore) who works
Physiological Society, with additional on new transcriptional and
contributions from Pfizer UK and the transductional strategies for targeting
Department of Physiology. The aims neurones. In his presentation, Dr Shu
were to raise awareness in the described advantages of the
physiological community of the recent recombinant baculoviruses for neuronal
achievements of this rapidly developing gene transfer. Presently, this type of
technology, to give researchers an vector is seldom used in neuroscience
opportunity to interact with some of the but this might change given the relative
world’s leaders working in the area and, ease of its production, efficient gene
finally, to facilitate collaborations delivery into central neurones and
between laboratories around the world. relatively large packaging capacity.
Central neurones transduced with cell-type specific
Gratifyingly, this turned out to be a viral vectors
Sebastian Kügler (Department of
truly international meeting with Neurology, University of Göttingen,
contributions from Germany, Germany) then gave an overview of his
Singapore, Switzerland, the UK and the
Viral gene transfer in work on adeno-associated viral vectors.
USA. Bristol seemed to be the right
place for this event given that several
neuroscience: new tricks of This vector is currently one of the
favourites in the field of gene therapy.
large research groups in this University the trade Dr Kügler illustrated its use in his
are using viral vectors in a variety of A Physiological Society Focused studies on neuroprotection. After the
research programmes ranging from Meeting held at the University of lunch break and poster session,
central control of blood pressure to Bristol (4-5 September, 2004) Beverley Davidson (University of Iowa,
gene transfer into transplanted blood USA) spoke of virally mediated
vessels. gene/protein in gain-of function or loss expression of RNAi in vivo, which she
of function experiments. Moreover, is developing as a gene therapy tool for
Viral vectors provide an excellent targeted viral vectors open a whole new neurodegenerative diseases. Gene
opportunity to address the major method for specific genomic suppression using RNA interference has
challenge presented by the topic of experiments on phenotypically been one of the hottest scientific topics
physiological genomics. As Boron and identified neuronal sub-populations. of the last few years and Dr Davidson’s
Boulpaep recently put it: ‘Physiological work on siRNA has been published in
genomics (or functional genomics) is a The meeting ran over 2 days. On 4 the most prestigious biomedical
new branch of physiology devoted to September the invited speakers gave journals. James Uney (University of
understanding the roles genes play in their presentations. First, Markus Bristol) then spoke about regulatable
physiology… In order to grasp the Ehrengruber (University of Zürich, gene expression and presented his
function of a gene product, the Switzerland) addressed some new studies on tetracycline-regulatable viral
physiologist must retrace his steps back developments in the alfavirus family of gene expression systems. His talk was
up the reductionistic road and achieve vectors and described recent Semliki followed by Andy Baker (University of
an integrated inderstanding of that Forest virus vectors that have decreased Glasgow) who is developing an
gene’s function at the level of the cells, cytotoxicity. This development is interesting strategy to alter the tropism
organs and whole body’ (Boron WF, important because the original versions of viral vectors. This is achieved by
Boulpaep EL (2002). Medical of these vectors, used in previous modifications to the capsid proteins of
Physiology. Saunders). Indeed, being studies, are highly toxic for the adenoviral and adeno-associated viral
exceptionally efficient gene delivery transduced cells, which clearly vectors using peptide sequences derived
vehicles, viral vectors allow both compromises the credibility of the from a phage display approach.
expression of a transgenic protein or results that may be obtained. This Nicholas Mazarakis (Oxford
suppression of an endogenous lecture was followed by Wang Shu Biomedica, Cambridge) presented
recent developments in his company for
using lentiviral vectors for gene therapy
treatment of neurodegeneration in man.
He focused on feline immunodeficiency
virus derived vectors with
transductional properties altered using
alternative coat proteins. Lentivirus
derived vectors were also the topic of
Mohan Raizada’s talk (University of
Florida, USA). The University of
Florida is one of the leading world
From the left: Nicholas Mazarakis, Stephen White, Markus Ehrengruber and Sebastian Kügler relaxing at the
symposium dinner centres for viral vector development
Physiology News | No. 58 | Spring 2005 | www.physoc.org
8 PN BRISTOL FOCUSED MEETING/THE SENSES
and Dr Raizada spoke on his work
using lentiviral vectors to study
The Journal of Physiology
mechanisms underlying the generation
of essential hypertension. The final
symposium ‘The Senses’
speaker, A G Teschemacher (University
A Journal of Physiology
of Bristol), presented a wide variety of
applications of both adeno- and symposium on sensory physiology
lentivirus derived vectors based on her was held in San Diego on 22
own studies and those performed in October, 2004. The satellite
collaboration with Sergey Kasparov symposium to the annual meeting
and Julian Paton in the Department of of the Society for Neuroscience
Physiology, University of Bristol. brought together leading experts
Specifically, she described studies to highlight the similarities and
where phenotypically identified differences in processing
neuronal populations were genetically strategies for a variety of sensory
targeted using adeno- and lentiviral
systems such as vision, audition,
vectors for dynamic confocal imaging
and functional studies at the cellular somatosensation and olfaction.
and systems level.
A lot of progress has been made on the
In addition to these presentations, about very early stages of sensory processing,
two dozen posters were presented as indicated by a number of Nobel
during the lunch and tea breaks by Prizes over the past few decades. As a
various researchers attending the consequence, the process of converting empirical evidence. Along the same
symposium, as well as by the speakers. physical energy into the excitations of lines of space perception, Frank
This provided a further opportunity to sensory nerves is quite well understood. Bremmer (Marburg, Germany) showed
meet the speakers and discuss issues The biggest current questions are what how information from visual, auditory
relating to viral gene delivery from the kinds of features are extracted from the and somatosensory systems is
experts. The meeting was followed by information stream and how these are integrated in the parietal cortex of
dinner at one of Bristol’s finest used to recognize objects and guide monkeys and humans.
harbour-side restaurants. actions.
One of the current core questions in
On Sunday morning Bristol-based Several of the talks dealt with the sensory physiology is how
groups (Kasparov-Paton viral question of how elementary features are computations are performed in neural
laboratory in the School of Medical conveyed to the central nervous system. ensembles. Miguel Nicolelis (Durham,
Sciences and James Uney’s laboratory Ed Callaway (La Jolla, USA) pointed USA) showed state dependent
in the Dorothy Hodgkin Building) out how luminance and chromatic responses in the barrel cortex of awake
opened their doors to the speakers and information are conveyed to the visual behaving rats. Michael Shadlen is
any delegates. This provided a further cortex in separate pathways. Paul Fuchs investigating similar questions in awake
chance to see first hand experiments (Baltimore, USA) presented a detailed behaving monkeys, tracing the
with viral vectors and to discuss the model of time and intensity coding at complete sequence of steps from
different technologies being applied. the hair cell’s ribbon synapse in the sensory processing to decision making.
inner ear.
We believe that this meeting provided a The symposium was a big success in
great opportunity to gain novel insights Linda Buck (Seattle, USA), who was pointing out similar coding strategies
into the rapidly developing world of just recently awarded this year’s Nobel for converting elementary sensory
viral gene transfer and to discuss the Prize for physiology or medicine,* information into features for quite
newest developments in the field with discussed how the excitations of different sensory modalities. However,
some of the world’s leaders and to olfactory receptors are converted into it also made clear that we have quite a
establish closer contacts and new smells. Peter Mombaerts (New York, long way to go towards understanding
collaborations. USA) presented work on the genetic the crucial next steps from features to
basis of olfactory maps. objects and actions.
Sergey Kasparov
Julian F.R. Paton Probably even more important than Karl R Gegenfurtner
Department of Physiology, University of Bristol, UK recognizing things, sensory information Justus-Liebig-University, Giessen, Germany
is used to enable orientation in space and member of the Editorial Board, The Journal of
Physiology
and to form decisions about future
Papers from the Bristol symposium actions. David McAlpine (London, UK) *See Tim Jacob’s article on the Nobel
were published in the January issue of presented a new model of auditory Prize winners Linda Buck and Richard
Experimental Physiology (2005, 90.1) space perception and supporting Axel on p. 12 of this issue
Physiology News | No. 58 | Spring 2005 | www.physoc.orgLIVING HISTORY PN 9
The case of the misbehaving circuit
Stanley Salmons recalls the accident that replaced a paradigm
In 1965 I was pursuing a PhD in Eric The fast muscle nerve would still carry
Ashton’s anthropometry group in the intermittent high-frequency bursts, but I
Department of Anatomy at the believed that the much greater activity
University of Birmingham, developing imposed by the stimulator would have
micropower radiotelemetric techniques the dominant effect. I developed the
for recording muscle activity from stimulator and we did the experiment.
freely moving primates. On 15 The stimulated fast muscle became
September that year I tried a new type slower (Fig. 1). Later Frank Sréter and
of single-pulse generator. It proved hard I were to show that the physiological
to keep it stable, so it was unsuitable and biochemical effects of cross
for this application. It struck me, reinnervating a slow muscle could be
however, that it could form the basis of nullified if stimulation was used to
an implantable stimulator, with which restore its normal activity pattern
one could resolve the controversy about (Salmons & Sréter, 1976). I put forward
the nature of the neural influence on the notion of functional adaptation, and
muscle. this became the more favoured
paradigm (Salmons & Henriksson,
At that time there was a good deal of 1981).
Above: Brenda Russell (around 1976) interest in the cross-reinnervation
Below: Jan Henriksson (1998) experiments of Buller, Eccles and
Eccles. These, it was widely believed, Where are they now?
showed that the contractile
Gerta Vrbová is Emeritus Professor
characteristics of fast and slow muscles
of Developmental Neuroscience in the
were determined by chemotrophic
Department of Anatomy &
factors delivered via the motor nerves.
Developmental Biology, University
A competing view, championed by
College London.
Gerta Vrbová, held that this neural
influence was mediated by the different
John Gergely is Senior Scientist at
frequencies of impulse activity in these
the Boston Biomedical Research
nerves. Dr Vrbová had just joined the
Institute.
Department, so I suggested to her that
we use the (as yet unbuilt) stimulator to
Jan Henriksson is Professor and
activate a fast muscle with the
Joint Head of the Section for Exercise
continuous, low-frequency pattern
Physiology, Department of Physiology
normally found in slow muscle nerves.
and Pharmacology, Karolinska
Institute, Stockholm.
Brenda Russell is Professor of
Physiology, Biophysics,
Bioengineering and Medicine, and
Associate Vice Chancellor for
Research at the University of Illinois
at Chicago.
Larry Stephenson is Ford-Webber
Professor of Surgery and Chief of
Cardiothoracic Surgery for Wayne
State University, the Detroit Medical
Center and Harper Hospital.
Jonathan Jarvis is Reader in the
Department of Human Anatomy and
Figure 1. Single twitch contractions of rabbit tibialis anterior muscles. Upper trace: control. Lower trace: stimulated
at 10 Hz for 6 weeks (Salmons & Vrbová, 1969). Cell Biology, University of Liverpool.
Physiology News | No. 58 | Spring 2005 | www.physoc.org10 PN LIVING HISTORY
In 1977 I met Jan Henriksson, an
exercise biochemist, at an IUPS
meeting in Szeged. In discussion we
realized that exercise-induced and
stimulation-induced changes differed
only in degree (Salmons & Henriksson,
1981). Brenda Russell (at that time
Eisenberg), who had been a colleague
at University College London, was at
the same meeting; we decided to
establish the time course of
ultrastructural changes during fast-to
slow transformation (Eisenberg &
Salmons, 1981). Subsequently Jan,
working in Oliver Lowry’s lab,
confirmed that oxidative enzyme
activity rose and fell in the same way Larry Stephenson, a contemporary portrait
as Brenda had shown for mitochondrial
Figure 2. SDS-PAGE (tube gels) demonstrating the density (Henriksson et al. 1986). skeletal muscle, a technique that still
expression of slow myosin light chains (MLCs) after 10 During transformation to a stable 2A has immense potential for patients with
weeks of stimulation; co-electrophoresis was used to
confirm the identity of the bands. From left to right:
phenotype this biphasic response was heart failure, and in which my
control rabbit tibialis anterior muscle (TA), control absent, evidence of interaction between colleague, Jonathan Jarvis, has played a
soleus (SOL), stimulated TA, mixed TA + SOL, mixed the pathways underlying adaptive major role. Other clinical applications
stimulated TA + SOL (Sréter et al. 1973). change (Mayne et al. 1996). At first it have been: stimulation of paralysed
was hard to reconcile the adaptive (including denervated) muscles to
In Boston I worked with Frank Sréter capacity of muscle with the existence restore posture, movement, or
and John Gergely on the newly of discrete fibre types, but I used a ventilation lost through stroke or
discovered myosin light chains threshold model to explain both this spinal-cord injury; pacing of the
(MLCs). We found that slow MLCs and the sequence of changes that diaphragm in apnoeic babies; and
were induced by stimulation (Fig. 2). followed the onset and cessation of configuration of conditioned muscle
This was an exciting observation stimulation (Salmons, 1990). grafts as artificial sphincters. But it all
because it showed that muscle started with a badly behaved circuit.
stimulation elicited qualitative, as well A feature of the adaptive response of
as quantitative, changes in protein muscle to increased use was a dramatic Stanley Salmons
expression. My group and others, increase in fatigue resistance (Salmons Emeritus Professor of Applied Myology, Department of
particularly Dirk Pette’s in Konstanz, & Sréter, 1976). In 1979 Larry Human Anatomy and Cell Biology, University of
Stephenson, a cardiothoracic surgeon Liverpool, UK
subsequently added many other
proteins to this list. The underlying then in Philadelphia, asked me if such a
References
changes at gene level have yet to be muscle could do cardiac work. That Eisenberg BR & Salmons S (1981). The reorganisation of subcellular
unravelled, so the story is far from was the beginning of a 25-year structure in muscle undergoing fast-to-slow type transformation: a
stereological study. Cell Tiss Res 220, 449-471.
over. collaboration on cardiac assist from
Henriksson J, Chi MM-Y, Hintz CS, Young DA, Kaiser KK, Salmons
S, et al. (1986). Chronic stimulation of mammalian muscle: changes
in enzymes of six metabolic pathways. Am J Physiol 251, C614-
C632.
Mayne CN, Sutherland H, Jarvis JC, Gilroy SJ, Craven AJ &
Salmons S (1996). Induction of a fast-oxidative phenotype by chronic
muscle stimulation: histochemical and metabolic studies. Am J
Physiol 270, C313-320.
Salmons S (1990). On the reversibility of stimulation-induced muscle
transformation. In The Dynamic State of Muscle Fibres, ed. Pette D,
pp 401-414. Walter de Gruyter, Berlin.
Salmons S & Henriksson J (1981). The adaptive response of skeletal
muscle to increased use. Muscle Nerve 4, 94-105.
Salmons S & Sréter FA (1976). Significance of impulse activity in the
transformation of skeletal muscle type. Nature 263, 30–34.
Salmons S & Vrbová G (1969). The influence of activity on some
contractile characteristics of mammalian fast and slow muscles. J
Physiol 201, 535-549.
Sréter FA, Gergely J, Salmons S & Romanul F (1973). Synthesis by
fast muscle of myosin light chains characteristic of slow muscle in
Jonathan Jarvis and Stanley Salmons at the World Cardiac Bioassist Meeting, Paris, 2003 response to long-term stimulation. Nature 241, 17-19.
Physiology News | No. 58 | Spring 2005 | www.physoc.orgA SUMMER IN THE LIFE OF ... PN 11
A summer in the life of…
The Society’s Executive Committee Chairman shares
some of his scientific journeys
memorable sites. On arrival in Buenos
Aires, I had 45 min to find my way from
the international to the national airport to fly
on to Iguazu falls. A relatively stressful
journey by bus through what seemed like a
never ending line of traffic, but in the end I Above: Iguazu Falls, a natural boundary between
never expected to be so overwhelmed by the Argentina and Brazil (with Pepe, M-Carmen and
thundering noise of the numerous Chelo).
waterfalls. Other attractions of Buenos Aires
Below: Giovanni, Jose Viña (member of our
included sight-seeing at night, excellent International Sub-Committee, University of Valencia,
steak, and impressive displays of tango! Spain) and Guiseppe Poli (University of Torino, Italy)
David Yudilevich and Giovanni in the company of visiting the sights in Buenos Aires, Argentina.
Albert Einstein In June Tetsuro Ishii and I travelled to
Berlin as invited guests of the
I am currently Chairman of the Executive Hydroxynonenal Society. There we were
Committee of the Physiological Society and accommodated in the Hilton just opposite
Head of Graduate Research Studies in the the German and French Cathedrals and
Guy's, King's & St Thomas' School of Katharina Mahn provided an eye-opening
Biomedical Sciences at King's College tour of what was East Berlin, including the
London. The majority of my time is spent Berliner Dom and other sites.
on research, though I do thoroughly enjoy
interacting with the staff in the London and I flew to Valencia in July to meet up with
Cambridge offices of our Society. I am Jose Viña's research group in the
fortunate to have excellent research links Departamento de Fisologia. On this
with friends in Spain (Jose ‘Pepe’ Viña), occasion, my wife Lynn travelled with me.
Italy (Guiseppe Poli), Japan (Tetsuro Ishii Pepe took us on an inspired tour of
and colleagues), Brazil (Claudio Mendes Valencia, and we particularly appreciated
Ribeiro), Oxford (Clive Ellory), Edinburgh the visit to the market in the old part of
(Richard Sharpe) and numerous colleagues town. There Pepe was greeted at several
at King's and my closest collaborator market stalls and was given some of the
Richard Siow. finest fresh squid I have ever seen. It
transpired that these individuals were Pepe's
Rather than a 'week in the life of ...’, I patients, who he was treating for dietary
thought I would share some of my scientific conditions. Although we had a splendid
journeys during May to August 2004. dinner with Pepe and his family, we never
Before I start reminiscing about scientific did get to taste the freshly prepared squid!
travels, the photograph of colleagues in
front of the poster of Albert Einstein is quite My summer was rounded off in August with
dear to me. David Yudilevich cherished this an annual pilgrimage to Portugal, where my
poster brought from Chile to Queen family and I have spent our summer Above: Katharina Mahn (Giovanni's PhD student and
Elizabeth College, where he was Head of a now a postdoc with Rachel Tribe and Lucilla
holidays for the past 6 years. Later in
Department of Physiology until 1985. We Poston), originally from the Humboldt Universität in
November, with 'wanderlust' still in my Berlin, enjoys a beer or two with Tetsuro Ishii (Univ.
spent many hours in his office at blood, I set off for mainland China on Tsukuba, Japan) in the beautifully restored
Kensington discussing and arguing about behalf of the School of Biomedical Sciences 'Gendarmenmarkt' in Berlin.
science! On his retirement he presented the and the Society. One of my objectives was
poster to me and it now hangs in my office to discuss joint degrees and exchange of Below: Between travels abroad, I seem to find time to
at Guy's Campus. The recent joint meeting postgraduates with senior colleagues at field calls from the Society’s office and/or my
of the Physiological Society and Chilean Tsinghua University and Peking University. daughters.
Physiological Society at King's bears On behalf of the International Sub-
testimony to David's unique ability to foster Committee of our Society, I met with the
links between Chile and the UK. President and Meetings Secretary of the
Chinese Association of Physiological
Thanks to sponsorship from the Society, Sciences to explore the possibility of a joint
Pepe and I co-organized a symposium meeting in China in 2008. David Eisner, our
entitled Phytoestrogens and isoflavones: International Secretary, is now liaising
cell signalling and physiological action at further with colleagues in China.
the International Society for Free Radical
Research (SFRR-I) meeting in Buenos Giovanni E. Mann
Aires, Argentina in May. As with most of Academic Department of Physiology and
my trips abroad, I find moments to explore Cardiovascular Division, King's College London, UK
Physiology News | No. 58 | Spring 2005 | www.physoc.org12 PN THE NOBEL PRIZE
The Nobel Prize
Tim Jacob traces the route that Linda Buck and Richard Axel took to claim one of the
major uncollected prizes in sensory science – the secrets of the olfactory system
This year’s Nobel Prize for Medicine efforts came to nothing. Looking back
and Physiology was shared by Linda Axel has commented that this was
Buck (57) and Richard Axel (58) for because of the large number of odorant
their discovery of the olfactory receptor receptors, each of which was only
gene family. expressed at a very low level. Finally,
Buck made the breakthrough by
In 1991, after about 8 years of research making three assumptions. The first
effort, they published their landmark was that the odorant receptors were
paper in Cell in which they reported likely to be members of the 7
that they had succeeded in cloning 18 transmembrane G-protein coupled
different members of an extremely receptor family. The second was that
large multigene family that, they said, the odorant receptors themselves should
‘may encode odorant receptors’. This exhibit significant diversity and belong
family we now know is the largest so to a multigene family and the third that
far discovered and occupies about 3% their expression be limited to the
of the human genome. In order to olfactory epithelium. Homologues of
achieve this breakthrough they made the 7-TM domain superfamily were
some educated guesses that narrowed amplified from olfactory epithelial
the odds – in other words luck played a RNA. Using restriction enzymes to
part. digest the PCR product they looked for
Linda Buck (top) and Richard Axel fragments that consisted of a mixture of
Following publication they went their DNA sequences arguing that a
separate ways. Axel remained at polymerase chain reaction (PCR) that multigene family would generate a set
Columbia where he has been since his finally unlocked the secrets of the of DNA fragments whose molecular
undergraduate studies. Buck moved to olfactory system. weight would be far greater than the
Harvard for 10 years and then original PCR product. The restriction
westward in 2002 to the Fred From 1982-1991 Linda Buck was a digestion of a single species of DNA,
Hutchinson Cancer Research Center in postdoctoral fellow in Richard Axel’s on the other hand, would generate a set
her home town, Seattle. Although lab. The Howard Hughes Medical of fragments whose molecular weights
working separately, they both Institute (HHMI) was supporting both would sum to that of the original PCR
demonstrated, in different publications, of them during this period. To product.
that each olfactory receptor neuron understand the olfactory system it was
(ORN) expressed only one type of necessary to discover how the system Stuart Firestein, a colleague at
olfactory receptor and that each ORN responded to thousands of different Columbia and another major player in
expressing the same receptor sent its molecules of different shapes and sizes. olfactory research has pointed out that
axon to the same place in the olfactory Did it achieve this with a restricted set this work would probably not have
bulb. Buck went on to publish the idea of promiscuous receptors or a large been possible without HHMI support:
of a ‘combinatorial code’ that is the number of relatively specific receptors? ‘It would have been hard to do this if
currently accepted view of how And second, how did the brain utilise you were required to produce regular
different odours are discriminated. these responses to discriminate between publications to support your next
odours? In 1983, Kary Mullis at Cetus grant,’ he said. Buck was a 44-year old
The secrets of the olfactory system had Corporation conceived of a way to start postdoc at the time of the publication of
long been one of the major uncollected and stop a polymerase's action at their Cell paper with 10 papers to her
prizes in sensory science. Over the specific points along a single strand of credit – only three as first author. The
years there had been many theories DNA. The result was PCR for which he HHMI has nurtured 13 Nobel Prize
attempting to explain how/why was awarded the Nobel Prize for winners since it was established in
molecules smell including molecular Chemistry in 1993. So, instead of 1984 and Columbia University itself
vibration, piezo electric currents, hunting for the receptor proteins has produced a steady stream of Nobel
membrane diffusion pores and directly, Axel and Buck used PCR to Laureates, 72 in all. Twenty-one of
molecular shape. Most of them were look for genes that contained these are in Physiology and Medicine,
empirical and did not lend themselves instructions for proteins found only in including Eric Kandel (2000).
to scientific test. It was the advent of the olfactory epithelium. It was a Tim Jacob
molecular biology and, in particular, technique in its infancy and at first their University of Cardiff, UK
Physiology News | No. 58 | Spring 2005 | www.physoc.orgFEATURES PN 13
50 years of caveolae – a round-up
It is 50 years since the first microscopic observation of the tiny flask-shaped
plasmalemmal invaginations termed caveolae. Only in the last decade, however, with the
discovery of the family of caveolin proteins that are integral to these organelles, have we
begun to unravel the possible physiological roles of these enigmatic structures
The decade following the second world The missing link identified
war proved to be a prolific period for The discovery at the turn of the 1990s
the application of electron microscopic of a protein component of caveolae,
techniques to the analyses of the termed caveolin, was to revolutionise
ultrastructure of tissues and cells. the study of these organelles. Caveolin
Through such endeavours Pallade is actually a family of protein
(1953) and Yamade (1955) became the molecules of mass 21-24kDa with three
first workers to describe an unusual main mammalian isoforms
feature of the plasma membrane of (imaginatively termed caveolin-1, -2
endothelial and epithelial cells: they Michael Taggart and –3). There are two and three
found that the plasmalemma, far from isoforms, respectively, of caveolin-1 (α
being uniform, often gave the muscle as early as the 1970’s. The and β) and caveolin-2 (α, β, γ).
appearance of regular, Ω-shaped observations of a close appositioning of Whereas these show a wide tissue
invaginations; Yamade termed these caveolae to elements of the distribution, caveolin-3 has a much
structures ‘caveolae intracellulares’ sarcoplasmic reticulum (the major more restricted appearance, being
(see Inset). Ever since, the source of releasable organellar Ca2+), predominant in striated muscle cells.
physiological roles of these organelles and immunogold localisation of a Ca2+- Crucially, transfection of non-caveolin
has perplexed and fascinated in equal ATPase to caveolae, were instrumental containing cells, which had no
measure. What follows is a very brief in developing this idea. By and large, morphological appearance of caveolae,
round-up of this topic but for more however, experimental evidence in with caveolin-1 (or -3) induced the
extensive background the reader is support of these different roles of formation of Ω-shaped invaginations.
directed to the reference list at the end caveolae was observational and Subsequently, an interaction of high
of this article. progress was hindered by the lack of a molecular weight caveolin oligomeric
definitive molecular marker of caveolar complexes with cholesterol appeared to
The early sightings structures. be key to the formation of caveolae.
As caveolae were initially discovered in
cells lining the lumenal surface of Caveolins, however, quickly established
hollow organs, a role in themselves as something more than just
macromolecular transport phenomena ‘Endothelial cells ... possess … a plasma membranous structural
was postulated, including capillary large number of vesicles components. Biochemical
concentrated immediately under
permeability and transcytocis and the characterisation studies, including
the cell membranes facing both
regulation of cellular free cholesterol the capillary lumen and the immunoprecipitation, began to
flux. With regard to the latter, precapillary spaces. The vesicles, highlight a multitude of signalling
cholesterol sequestering agents have sometimes tightly packed in molecules co-localising with caveolin
layers, are speherical in shape and
been known for many years to disrupt 1. Furthermore, a small 20 amino acid
measure ~650A in diameter. Many
the appearance of caveolae. of these appear to open at the peptide derived from caveolin-1 was, in
Subsequently, caveolae were found to surface of the cell membrane.’ in vitro assays, found to bind to a
be prominent, occupying approximately Palade (1953) whole host of signalling molecules that
J Appl Physics 24, 1424
25% of plasmalemmal surface area, in act downstream of receptor-coupled
many other cell types including ‘Some of these vesicles seem to membrane effectors. In cardiovascular
adipocytes, smooth muscle (Fig. 1) and communicate with the lumen cells, for example, these included
through openings in the cell
cardiac cells (with a few notable PKCα, rhoA, ERK, and nitric oxide
membrane covering the
exceptions being lymphocytes and microvillus. These small cave-like synthase (NOS). Binding to this
some cell lines such as HepG2 cells). indentations of the cell wall…... peptide, termed the caveolin scaffolding
This wide distribution necessitated resemble similar structures domain, even altered the enzymatic
described along the inner and
consideration of this idea that caveolae activity of these signalling molecules
outer cell membrane of capillary
might be important for a number of endothelial cells by Palade. It is and, once introduced into live cells,
functions. Regulation of here proposed to speak of such a altered functions as diverse as cytosol
transmembrane ion fluxes important for recess or pocket as a ‘caveolae membrane protein translocations,
intracellulares’
cellular excitability was one possible Yamade (1955)
cardiac myocyte beating, flow-induced
function ascribed to caveolae in smooth J Biophys Biochem Cytol 1, 445-458 arterial dilation and eNOS activation.
Physiology News | No. 58 | Spring 2005 | www.physoc.orgYou can also read
