(1942 – 202?)
I was trained as a biological scientist, and lived the life of a 20th century academic, teaching and pursuing original research, from my bachelor's degree (B.A. in Botany, in 1964) to my retirement in (2006). Of what use that was to my country I dare not speculate, but I hope that I was worth my salary. Since retiring from science I have sustained my self-esteem with the thought that some of the little jottings I post on my 'blog' [Ref. 1] could be of some use to the wider world. Anyone with a computer can read them, and if equipped with the right mental furniture, could surely understand them. Like my professional publications, they are original, in-so-far as they originated in my brain. They hatched and grew in that peculiar mixture of ideas, facts, images and memories that have collected in my brain over the last 84 years. Several of these ideas will have occurred to many people, and others of these ideas will have occurred to a few. However, I hope that most readers will find something novel. It is possible that one or two ideas are unique. I am not claiming any sort of superiority; simply the uniqueness that is inevitable in people of my age.
The 380-odd posts should be sifted and the best of them selected. But who am I to judge? I am prejudiced. I need a sympathetic biographer, or a literary agent.
Two of my more valuable posts (in my eyes) are those in which I summarise the life's work and claim-to-fame of senior colleagues. (These are easily found on my 'Blog' by using the Search box.) The first is my "In Memoriam: Peter Mitchell", a paper commissioned by the editors of Molecular Microbiology soon after the somewhat unexpected death of Nobel Prize-winner Peter Mitchell at the age of 71 [Ref. 2]. The second is the oration I was invited to give at the funeral of my colleague and departmental head, Professor Kenneth Burton FRS [Ref. 3]. In both cases I wrote from a privileged position; shear proximity allowed me access to special information. I think I captured, and preserved for posterity, some unique insights into the minds of these two prominent scientists.
While I was congratulating myself that two at least of my pieces were surely worthwhile, I wondered who might be asked to write my "In Memoriam", or speak at my funeral. Who would know, and sufficiently understand? Fame has never been my objective; "truth" rather. I suppose I naïvely assumed that some recording angel was taking notes. But perhaps that was not the case. What if it is up to me to make a note?
In my last few working years I twice had a chance to present myself to younger colleagues. In 2002 I was asked to introduce myself to the research group of Professor Wei Hua-Wei at Yang Ming university, Taipei, Taiwan. And again, four years later I spoke to the research group of Professor Keith Garlid, at the Department of Biology, Portland State University, Oregon, USA. I probably still have the PowerPoints somewhere on a laptop or 'memory stick'. In Taiwan I presented my best known work (on the co-transport of Lactose with H+). 'Ken' (one of the senior post-doctoral students) said that it was text-book knowledge; he never thought of it as 'research'.
Here I propose to write notes for my hypothetical obituarist, describing some of the contributions to science of which I am most proud, (or most afraid that they will escape the notice of posterity).
1. West, I.C. & Stein, W.D. (1973) Biochim. Biophys. Acta; 308(7):161-7,"The kinetics of induction of 𝛃-galactoside permease"
After my postdoctoral year with a Nuffield Scholarship at University College London, learning maths, organic chemistry, physiology and biochemistry, I applied for a government funded research fellowship to test Peter Mitchell's suggestion that the accumulation of lactose in E. coli was by lactose-proton symport, explicitly in the laboratory of Dr. Wilfred D. Stein in Manchester. When I got to Manchester in August 1968, Stein told me that he had already tested the co-transport idea, and found it wrong. (It turned out that he did not understand the hypothesis; he assumed the co-ion to be Na+ as in animals.) But he was excited by another idea – that we could follow the synthesis of the lactose carrier protein and its insertion into the plasma membrane of the bacterium.
Wilf Stein's idea was that the nascent polypeptide chain of lactose permease in the bacterium E. coli might take a measurable amount of time to fold and insert itself into the cell membrane. The joint project was named "Project P" (for proto-permease). But Wilf left for Jerusalem early in 1969, before we had got the experiments to work. The framework of the experimental approach (adding inducer and following the synthesis of active protein product) and the mathematics of building up a steady-state pool of messenger RNA were both due to Adam Képès [4], an Hungarian working in Paris, who had done equivalent experiments on the synthesis of β-galactosidase (the first protein-coding gene in the lac-operon). I did the experiments (in 1969, after Wilf Stein had left) and wrote the paper (in 1973); but the contribution that I am proud of, that made the experiments possible, was that of increasing by a factor of 10 the sensitivity of the permease assay (by extracting the yellow-coloured nitro-phenol product into butanol). Even that was only partly my idea; I had done something similar in applying the 'Marsh assay' for inorganic phosphate during my thesis work some 2 - 3 years earlier.
Our conclusion was that there was no measurable delay between synthesis and the appearance of functioning permease.
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2. West, I.C. (1970) Biochem. Biophys. Res. Commun.; 41(3):655-61; "Lactose transport coupled to proton movements in Escherichia coli".
There is no doubt that this ought to be my most cited paper, as it was the first to report the coupled inflow of 𝛃-galactosides with protons on the E. coli lactose permease; according to the prediction made 7 years earlier by Peter Mitchell. The idea being tested was Mitchell's. And the experimental set-up (a stirred, anaerobic, suspension in which was inserted a glass pH electrode) had been developed by Mitchell and Moyle for their work on rat-liver mitochondria. But the idea of driving an inflow of H+ by causing an inflow of sugar was uniquely mine; and the experiments were performed in my lab in Manchester. Moreover, I thought it prudent to inhibit glycolysis with iodoacetate; not something considered by Mitchell and Moyle, as mitochondria do not operate glycolysis.
During the work I received a phone call from an excited Peter Mitchell wanting to know how the experiments were going. He gave me a helpful tip, by pointing out that it is not possible to carry many H+ ions into each cell unless there is a permeating anion that can flow in to neutralise the charge (or a counter-flowing permeant cation). Mitchell suggested adding thiocyanate (SCN-), which certainly gave better traces.
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A month of two later, Mitchell invited me to join the tiny team of two at his private laboratory in Cornwall, and arranged to pay me a post-doctoral salary. I was able to confirm and extend my work on proton-coupled transport processes in E. coli., showing one proton per lactose molecule, showing Na+/H+ antiport, and a H+ translocating ATPase. I published, as first author, in a number of joint papers, where my role was somewhat hidden by the giant shadow of my boss.
In 1973 I got married, moved to a Demonstratorship in Biochemistry at Cambridge, and a teaching Fellowship at Clare College, where I was Director of Studies in Biochemistry for first-year medical students, and science students in all three years; I was allowed to find external supervisors for some of my charges, but was expected to do a full timetable of supervising myself. I had to learn a lot of Chemistry and Biochemistry and, for my first year, I sat in on most of the courses of lectures that my students were taking. I also assisted running practical classes devised by senior colleagues. And devised projects for final-year students. On top of that, the lab that I shared with Tim Hunt, Richard Jackson and Tony Hunter, was gutted by fire (the last, I hope, of a series of fires caused by putting solutions saturated with ether into a domestic refrigerator and left overnight). On top of that I was attempting to apply the methods of protein chemistry to an intrinsic membrane protein – the lactose permease.
In those Cambridge years I learned a lot of chemistry and biochemistry, met a number of gifted scientific colleagues, played quartets with Martin Kamen and Robin Hill's wife Priscilla, violin-piano duets and trios with Malcolm Dixon and Sir Rudolph Peters; and enjoyed the amazing privilege of a college fellowship. But I published nothing.
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3. West, I.C. & Page, M.G.P. (1984) J. theoret. Biol.; "When is the outer membrane of Escherichia coli rate-limiting for uptake of galactosides?".
In 1976, on the birth of my daughter and alarmed at the approaching termination of my Demonstratorship, I moved to a tenured post in the Biochemistry Department at the University of Newcastle upon Tyne. There, teaching, administration, and family life kept me occupied. The chemical work did not progress, and I turned to kinetics.
My able post-doc, Malcolm Page, produced some good data on the inflow of o-nitrophenyl-𝜷-galactoside at various pH values. I asked him if there was any evidence that the sieve-like outer membrane might interfere with the kinetic behaviour of the permease imbedded in the inner membrane. Malcolm said "yes, there was! But only at very low concentrations." Under those conditions, the kinetics of galactoside inflow departed from saturable (i.e. enzyme-like) kinetics and became first-order, diffusional kinetics. Malcolm used the linearised Eadie-Hofstee plot, where "saturation kinetics" gives a straight line sloping down to the right, while "diffusion kinetics" gives a vertical line. (See Figure. 1)
"Because", I realised, "we are plotting rate against the known external concentration of substrate ([s]), whereas the permease is experiencing a somewhat lower concentration in the inter-membranal space. In that case, if we assume the lactose permease continues to follow the enzyme-like saturation kinetics even at low substrate concentrations we could extrapolate the linear portion of the enzyme-like kinetics and, assuming first-order for the diffusion, we can read off the actual concentration in the periplasmic (inter-membranal) space." Malcolm agreed.
Years later, in 2005, I explained this to Keith Garlid's research group in Portland (Oregon). Keith scoffed. I retorted that using the rate of an enzymic reaction to determine the concentration of its substrate is a familiar technology; witness the 'glucose oxidase electrode', widely used by patients with diabetes.
We had found a miniaturised detector that could monitor the concentration of galactoside between the outer and inner membranes. It is normal practice for post-doc names to come first and senior names to come last on publications. Malcolm very courteously let my name go first on this paper.
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In 1983, faced with the retirement of Jennifer Moyle, Peter Mitchell contacted me again and asked if I would come back to the Glynn Research Institute to step into Jennifers's shoes. That would be a tall order, for Jennifer Moyle was a brilliant bench scientist, a commanding presence in the Institute, and had been Mitchell's colleague and 'right hand' for thirty years (1953-83). However, there was an ongoing debate in the scientific community about the number of H+ ions (i.e. protons) translocated per O atom reduced to water during respiration in mammalian mitochondria, After discussion with my wife (as this would involve moving the family) I agreed to return to Glynn, provided I was a co-grant-holder, and if Newcastle University would give me 5 years 'Leave of Absence'. Mitchell and Newcastle both agreed.
After training as a botanist for 6 years, then working for 15 years on transmembrane transport in bacteria I was now switching to work (a) on respiration, and (b) in mammalian mitochondria; I had considerable catching up to do. My one advantage over Jennifer Moyle lay in the fact that I was not so loyal to the genius of Peter Mitchell; I was more independent minded.
4. West, I.C. (1986) Biochim. Biophys. Acta, 849, 236-42; "A theoretical analysis of the effect of phosphate on apparent H+/O stoichiometries in oxygen-pulse experiments with rat liver mitochondria".
The specific problem was the number of H+ ions (i.e. protons) translocated outwards across the mitochondrial membrane (per O atom reduced) during the reduction of oxygen to water. On the basis of Jennifer Moyle's very consistent measurements (see below), Peter Mitchell thought 6 H+ were ejected per O atom if the electrons came from NADH2. He had consequently conceived a mechanism which permitted, and indeed forced a 6:1 stoichiometry on the process. Brand, Reynafarge and Leheninger [Ref. 5] found more than 6 protons per O atom, in fact 8 or 9. Lehninger's group suggested that phosphate was carrying a few protons back into the mitochondrial matrix so fast that they escaped notice by the slightly sluggish pH electrode. If the thiol-reactive reagent N-ethyl-maleimide (NEM) was present, known to inhibit phosphate-plus-H+ transport, they could better determine the true number of ejected protons.
Mitchell rejected that explanation as he believed that he and Jennifer Moyle had considered, and eliminated, that possibility twenty years previously by measuring the extra-mitochondrial phosphate concentration and finding there was not enough [Ref. 6]. No one doubted that the reactive NEM inhibited phosphate transport, but Mitchell suggested it must be doing something else as well (a plausible escape-route to rescue his mechanism).
At the Glynn Laboratory, in Cornwall, all definitive experiments were done by the disciplined and punctilious Dr. Jennifer Moyle. At precisely 1 o'clock she ate a sandwich and an apple at her desk, at 1.30 she went for a walk; at 2.00 she started the experiments. She got very consistent results, averaging 5.88 (+/- 0.12) H+/O [Ref. 6]. Also working in the Glynn Laboratory was Peter Mitchell's very able technician, Roy Mitchell (not a relation, but a Cornishman, a fundamental Christian, and an excellent scientist). Roy confirmed the effect of NEM. But Roy noticed that (in the absence of NEM) experiments done before 2 o'clock gave higher H+/O stoichiometries, while those done later gave lower stoichiometries. He suspected that, while the mitochondrial suspension was sitting on ice in the cold-room, phosphate was gradually leaking out into the suspending medium.
Behind Roy's back, Jennifer would make a face and tap her head implying that Roy's fundamental religious beliefs impugned his judgment and scientific reliability. Ironically it was (in my view) the other way round; it was Jennifer's faith in Mitchell's theoretical acumen that blinded her to some of the possibilities.
I saw my mission as peculiar, perhaps unique. All scientists seek 'truth'; they try to compile evidence (experimental or observational) that is consistent with one explantation while being inconsistent with alternatives. I felt that we already knew the truth, or at least that we had an excellently economical explanation of the observations; my mission was to persuade Peter Michell. The world needed to hear it from Peter himself.
If a proton motive force could cause the very rapid uptake of phosphate with a proton, perhaps Jennifer's finding of little external phosphate was correct, simply because it had mostly been taken up already in the 2 – 3 seconds while she plunged her syringe into the suspension to extract a sample for measurement.
I decided to sample the suspension and separate mitochondria from medium, not extra quickly, but instead extra carefully; maintaining strictly anaerobic conditions. I capped the anaerobic suspension tube with a layer of anaerobic butanol containing methylene blue made colourless with a grain of sodium dithionite. I flushed my syringe with anaerobic medium and, after filling it with anaerobic suspension, injected my sample under a layer of anaerobic butanol in a centrifuge tube. Any entering oxygen would react first with the leuco-methyene-blue, and turn it blue; none entered. After centrifuging, to sediment the particles, the medium was found to contain quite a lot of phosphate. [7]
Additionally, I calculated that the amount of phosphate present would (in reaching equilibrium) conduct back into the mitochondria ⅓ of the ejected protons. It looked as though Brand et al. (and Roy Mitchell) were right about the effect of phosphate, while Peter Mitchell and the loyal Jennifer were wrong.
Thirty years later I was invited to contribute an assessment of the Classic Papers in the Biochemical Journal of 1967 by Mitchell and Moyle where I discuss the original Mitchell & Moyle papers and my subsequent re-assessment of the concentration of extra-mitochondrial phosphate [Ref. 6].
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5. West, I.C. (1989) Biochim. Biophys. Acta; 976, 182-189; "Triphasic reduction of bH and the absence of equilibration at the i-site of bc1, complex".
From my point of view, my greatest intellectual achievement took place in the stressful summer of 1988, when I dared to modify the famous 'Nernst equation' and I found myself in opposition to both Peter Mitchell and Peter Rich (a research colleague at the Glynn Research Institute and, after Mitchell's death, the director of the Institute).
Peter Mitchell had drawn my attention to the strange triphasic time-course of reduction of the high-potential b-cytochrome (bH) of the mitochondrial inner membrane, and suggested a possible mechanism; then he went on holiday. My 5-year leave of absence from Newcastle University was coming to an end. We had sold our Cornish house and bought another in Hexham. The family had returned to Hexham to be ready for the start of term in new schools, while I stayed on in digs, to complete my contract.
I quickly realised that Peter Mitchell's suggestion had already been ruled out. I had overheard conversations in the common-room between Peter Rich and David Moss who were woking on the analogous cytochrome bf complex of plant chloroplasts; I heard in particular of the "two-electron gate" that operates at photosystem II in the reduction of plastoquinone. I wondered if I could model the reported triphasic reduction of cytochrome b using only this concept of a tightly bound semiquinone radical. I collected up from the literature the relevant mid-point potentials for the redox centres in the isolated bc1 complex, and of the ubiquinone and duroquinone, both for the addition of one electron and for the complete two-electron reduction. Also estimates in the literature of the concentrations of the ubiquinone in the membrane; and I made educated guesses at 'on' and 'off' rate constants to calculate the binding of the oxidized, reduced and half-reduced quinone species. With these data I set up a computer model letting all reactions go to equilibrium while I gradually added electrons. If the half-reduced semiquinone radical were to bind very tightly to the complex, that would clearly change the observed midpoint potential, by a calculable amount; in free solution the quinone form is reluctant to take one electron (Em=-230mV), but if it were to take one electron it would become the semiquinone, and that binds tightly (ex hypothesi). As these affinities are reciprocal, the tight binding to the protein therefore 'pulls' the electron onto the quinone, raising its mid-point potential to more positive values. It all seemed promising.
I next wanted to calculate where a single electron would rest in the bc1 complex if it was shared between the two b haems, bH and bL. Now, at pH 7, bH (midpoint potential +80mv) has considerably more affinity for electrons than the bL (Em = –33mV), and is located nearer the lumen of the mitochondrion. Peter Rich suggested I use an equation he had derived and published 5 years previously [8]. However, that proved internally inconsistent.
Considering the work done in moving a mole of electrons from A- to B, using standard electro-chemical equations:
ΔG°' = zF(EmB - EmA) = -RT ln(KEQ)
However, standard electrochemistry assumes the concentrations of reactant and product do not change significantly when one molecule reacts or changes. But I was considering the equilibrium position in a single complex. Even if there is a mole of complexes, there is no pool of of bL at any potential; each complex (containing 1 electron) is isolated.
In the diagram below, a redox buffer of knows 'electron pressure' (relative to the hydrogen electrode, abbreviated as Eh) is in contact (via a mediator like PMS) with the cytochrome being studied. The redox potential (Eh) of the buffer is varied till the cytochrome in question is half-reduced; that potential is referred to as its mid-point potential (Em). Work is done on the system when a mole of electrons is moved from +80 mV to -40 mV; in quantity 11,412 Joule/mol. (Contrariwise, work is released when electrons are moved the other way.) But in those conventional (classical) calculations the source of the electrons remains at the constant potential of electrons in the buffer reservoir. It seemed to me obvious that, in the isolated bc1 complex, the work required to move the electron would be considerably more than if it were replaced rapidly from the reservoir. How much more? Intuitively one could suggest, twice as much work, on the following argument. In the isolated complex, when an electron is moved from bH to bL, a positive 'hole' is moved the opposite way, from bL to bH. Using that value, my modelling equations fitted.
Redox Buffer (Eh) ⬄ PMS ⬄⎛bL⊖ ⥂ ⊚bH ⎛ ⬄ PMS
I shared the idea with my two post-doctoral colleagues (Roy Mitchell and John Moody) in our communal office. Roy agreed immediately and added a further strand of argument to support the idea. He pointed out that a population of isolated complexes each carrying one electron would not have the same composition as in the in the presence of a reducible and mobile electron-carrier like PMS; such a carrier would equilibrate the electrons, and some complexes would have two electrons and some none.
When Peter Mitchell returned from holiday I explained all this to him, and how Peter Rich disagreed. He said he thought Peter Rich was right, and I wrong. I reminded him that my previous paper, where we had jointly discussed the rationale, but I alone had done the experiments, analysed the data, and written the paper; that paper had come back from referees with the comment that it was "another nice paper by Rich & Mitchell". I was completely ignored. So I asked if I might publish this work under my own name, as it was a project that had no direct input from him, and was directly contradicted by Peter Rich. He was furious. I left the room.
The next morning Peter Mitchell came up the spiral staircase to our first floor office and asked me if I could explain my theory again. He said he now though that I was correct, and conceded my request. My 'Triphasic' paper is single authored.
Three months later, when I was back in the North of England, my marriage in ruins, I received a letter from Peter Rich admitting that he had been wrong.
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6. West, I.C. (2000) Diabet. Med. 17: pp. 171–180. "Radicals and oxidative stress in diabetes".
Not only my marriage, for my career also was in ruins. I stumbled about for a few years. A colleague working on the abnormal Na/Li exchange in erythrocytes from patients suffering various diseases, asked me if I would help him think about his results. He very generously put my name on the half dozen papers that resulted. [9]
When I was asked to take over a lecture course on Oncogenes, I got a little bit interested in carcinogens, P450, P-glycoprotein. It occurred to me that the strangely wide substrate specificity of P-glycoprotein might be because its original and 'intended' substrates were steroids being secreted by the adrenal cortex, an idea that appealed to Tim Hunt as editor of Trends in Biochemical Sciences [10]. However, it was oxygen free radicals that provided the theme for the last 15 years of my research career.
From the standpoint of a bioenergeticist, the leakage of unpaired electrons from the respiratory chain onto ambient oxygen atoms had represented a source of inefficiency; a slippage, a failure to extract useful work from these high-energy electrons. But in the context of oncogenes, the reduced oxygen radicals appear as dangerously reactive, and therefore highly damaging, particles. My interest was aroused, and I offered a course of lectures on Oxygen; its production from water, in photosynthesis, its reduction back to water in respiration, and the handling of radicals to minimise, but also to utilise, their damaging properties.
What I think must be my second most cited paper is this one that came out in the millennial year 2000; it arose out of my lectures. I read that streptozotocin, known to me for decades through its ability to mimic type 1 diabetes mellitus in rats, was also well known as generating oxygen radicals. What if radicals trigger damage to the pancreas, perhaps because of low endogenous activity of protective pathways (superoxide dismutase, vitamin E, etc.); specifically in the pancreas? The relevance of radicals in diabetes remains vague, or perhaps a better word would be 'diffuse'. The triggering of susceptible genotypes into flagrant diabetes is stochastic.
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[Refs. 11, 12, 13, 14, 15]
When my paper came out in 2000, oxygen free radicals were still viewed with suspicion by 'solid', 'weighty' scientists, and I was warned that I would be viewed as a peddler of 'snake oil'. Since then oxygen radicals have become mainstream; certainly as liabilities, but also as useful signalling molecules. And most house-wives are on first-name terms with anti-oxidants. My knowledge of oxygen chemistry helped add five more papers to my curriculum vitae [11, 12, 13, 14, 15], papers in which I contributed only a small portion of the intellectual content, and none of the experimental work.
This résumé more-or-less sums me up, I guess; a jack-of-all-trades, spread too thinly to impress any one person.
References
[1] https://occidentis.blogspot.com/
[2] West, I.C. (1992) Mol. Microbiol.;6(23):3623-5.
[3] West, Ian C. (2011) The Biochemist 33(2):64-65; "Kenneth Burton FRS (1926–2010)"
[4] Adam Képès & Simone Beguin (1966) Biochimica. et Biophysica. Acta (BBA) 123, pp. 546-560.
[5] Brand, M.D., Reynafarje, B. & Lehninger, A.L. (1976) J. Biol. Chem.; 251: pp. 5670-9.
[6] West, I.C. (2015) Biochemist, Volume 37: pp. 47-50. "Classic papers on the quantification of respiratory proton ejection."
[7] Mitchell, Roy, West, I. C., Moody, A.J., & Mitchell, Peter (1986) Biochimica. et Biophysica. Acta; 849, pp. 229-235. "Measurement of the proton-motive stoichiometry of the respiratory chain of rat liver mitochondria: the effect of N-ethylmaleimide".
[8] Rich, P.R. (1983) Biochimica. et Biophysica. Acta (BBA) 722, pp. 271-280
[9] Rutherford PA, Thomas TH, O'Kelly J, West IC, Wilkinson R. (1996), Nephron. 72(2):184-8. "Thiol group control of sodium-lithium countertransport kinetics in uraemia: evidence of a membrane abnormality affected by haemodialysis."
[10] West, I.C. (1990) Trends Biochem Sci., 15: pp 42-46, "What determines the substrate specificity of the multi-drug-resistance pump?"
[11] Dioudis C, Dimitrios G, Thomas TH, West IC. (2008)
Hippokratia. 2008 Jul;12(3):162-7. "Abnormal glyceraldehyde-3-phosphate dehydrogenase binding and glycolytic flux in Autosomal Dominant Polycystic Kidney Disease after a mild oxidative stress."
[12] Andrukhiv A, Costa AD, West IC, Garlid KD. (2006), Am J Physiol Heart Circ Physiol. 2006 Nov;291(5):H2067-74. Epub 2006 Jun 23. "Opening mitoKATP increases superoxide generation from complex I of the electron transport chain."
[13] Costa AD, Jakob R, Costa CL, Andrukhiv K, West IC, Garlid KD. (2006)
J Biol Chem. 2006 Jul 28;281(30):20801-8. Epub 2006 May 23.
"The mechanism by which the mitochondrial ATP-sensitive K+ channel opening and H2O2 inhibit the mitochondrial permeability transition."
[14] Costa AD, Quinlan CL, Andrukhiv A, West IC, Jabůrek M, Garlid KD. (2006)
Am J Physiol Heart Circ Physiol. 2006 Jan;290(1):H406-15. Epub 2005 Sep 2. "The direct physiological effects of mitoK(ATP) opening on heart mitochondria."
[15] Costa AD, Garlid KD, West IC, Lincoln TM, Downey JM, Cohen MV, Critz SD.
Circ Res. (2005), Aug 19;97(4):329-36. Epub 2005 Jul 21. "Protein kinase G transmits the cardioprotective signal from cytosol to mitochondria."
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