The envenomation of general physiology throughout the last century.

Toxins are the poisonous products of organisms. Toxins serve vital defensive and offensive functions for those that harbor them: stinging scorpions, pesticidal plants, sanguinary snakes, fearless frogs, sliming snails, noxious newts, and smarting spiders. For physiologists, toxins are integral chemical tools that hijack life's fundamental processes with remarkable molecular specificity. Our understanding of electrophysiological phenomena has been transformed time and time again with the help of some terrifying toxins. For this reason, studies of toxin mechanism are an important and enduring facet of The Journal of General Physiology (JGP). This Milestone in Physiology reflects on toxins studied in JGP over its first 100 years, what they have taught us, and what they have yet to reveal

Modeling effects of L-type ca(2+) current and na(+)-ca(2+) exchanger on ca(2+) trigger flux in rabbit myocytes with realistic T-tubule geometries.

The transverse tubular system of rabbit ventricular myocytes consists of cell membrane invaginations (t-tubules) that are essential for efficient cardiac excitation-contraction coupling. In this study, we investigate how t-tubule micro-anatomy, L-type Ca(2+) channel (LCC) clustering, and allosteric activation of Na(+)/Ca(2+) exchanger by L-type Ca(2+) current affects intracellular Ca(2+) dynamics. Our model includes a realistic 3D geometry of a single t-tubule and its surrounding half-sarcomeres for rabbit ventricular myocytes. The effects of spatially distributed membrane ion-transporters (LCC, Na(+)/Ca(2+) exchanger, sarcolemmal Ca(2+) pump, and sarcolemmal Ca(2+) leak), and stationary and mobile Ca(2+) buffers (troponin C, ATP, calmodulin, and Fluo-3) are also considered. We used a coupled reaction-diffusion system to describe the spatio-temporal concentration profiles of free and buffered intracellular Ca(2+). We obtained parameters from voltage-clamp protocols of L-type Ca(2+) current and line-scan recordings of Ca(2+) concentration profiles in rabbit cells, in which the sarcoplasmic reticulum is disabled. Our model results agree with experimental measurements of global Ca(2+) transient in myocytes loaded with 50 μM Fluo-3. We found that local Ca(2+) concentrations within the cytosol and sub-sarcolemma, as well as the local trigger fluxes of Ca(2+) crossing the cell membrane, are sensitive to details of t-tubule micro-structure and membrane Ca(2+) flux distribution. The model additionally predicts that local Ca(2+) trigger fluxes are at least threefold to eightfold higher than the whole-cell Ca(2+) trigger flux. We found also that the activation of allosteric Ca(2+)-binding sites on the Na(+)/Ca(2+) exchanger could provide a mechanism for regulating global and local Ca(2+) trigger fluxes in vivo. Our studies indicate that improved structural and functional models could improve our understanding of the contributions of L-type and Na(+)/Ca(2+) exchanger fluxes to intracellular Ca(2+) dynamics

Towards understanding the myometrial physiome: approaches for the construction of a virtual physiological uterus

Premature labour (PTL) is the single most significant factor contributing to neonatal morbidity in Europe with enormous attendant healthcare and social costs. Consequently, it remains a major challenge to alleviate the cause and impact of this condition. Our ability to improve the diagnosis and treatment of women most at risk of PTL is, however, actually hampered by an incomplete understanding of the ways in which the functions of the uterine myocyte are integrated to effect an appropriate biological response at the multicellular whole organ system. The level of organization required to co-ordinate labouring uterine contractile effort in time and space can be considered immense. There is a multitude of what might be considered mini-systems involved, each with their own regulatory feedback cycles, yet they each, in turn, will influence the behaviour of a related system. These include, but are not exclusive to, gestational-dependent regulation of transcription, translation, post-translational modifications, intracellular signaling dynamics, cell morphology, intercellular communication and tissue level morphology. We propose that in order to comprehend how these mini-systems integrate to facilitate uterine contraction during labour (preterm or term) we must, in concert with biological experimentation, construct detailed mathematical descriptions of our findings. This serves three purposes: firstly, providing a quantitative description of series of complex observations; secondly, proferring a database platform that informs further testable experimentation; thirdly, advancing towards the establishment of a virtual physiological uterus and in silico clinical diagnosis and treatment of PTL

Sphingosine 1-phosphate in renal diseases

Because of its highly bioactive properties sphingosine 1-phosphate (S1P) is an attractive target for the treatment of several diseases. Since the expression of sphingosine kinases as well as S1P receptors was demonstrated in the kidney, questions about the physiological and pathophysiological functions of S1P in this organ have been raised. In this review, we summarize the current state of knowledge about S1P-mediated functions in the kidney. A special focus is put on S1P modulated signal transduction in renal glomerular and tubular cells and consequences for the development and treatment of several kidney diseases, diabetic nephropathy, glomerulonephritis, ischemia-reperfusion injury, as well as for Wilms tumor progression

G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease

G protein-coupled receptor 35 (GPR35) is an orphan receptor, discovered in 1998, that has garnered interest as a potential therapeutic target through its association with a range of diseases. However, a lack of pharmacological tools and the absence of convincingly defined endogenous ligands have hampered the understanding of function necessary to exploit it therapeutically. Although several endogenous molecules can activate GPR35 none has yet been confirmed as the key endogenous ligand due to reasons that include lack of biological specificity, non-physiologically relevant potency and species ortholog selectivity. Recent advances have identified several highly potent synthetic agonists and antagonists, as well as agonists with equivalent potency at rodent and human orthologs, which will be useful as tool compounds. Homology modeling and mutagenesis studies have provided insight into the mode of ligand binding and possible reasons for the species selectivity of some ligands. Advances have also been made in determining the role of the receptor in disease. In the past, genome-wide association studies have associated GPR35 with diseases such as inflammatory bowel disease, type 2 diabetes, and coronary artery disease. More recent functional studies have implicated it in processes as diverse as heart failure and hypoxia, inflammation, pain transduction and synaptic transmission. In this review, we summarize the progress made in understanding the molecular pharmacology, downstream signaling and physiological function of GPR35, and discuss its emerging potential applications as a therapeutic target

Drugs Affecting 5-HT Systems

Seminar transcriptIt was in the very early hours of a February morning in 1977 that I first looked down the microscope and saw yellow fluorescence, characteristic of 5-hydroxytryptamine (5-HT) in frozen sections of Octopus brain. After struggling for two years with the capricious fluorescence histochemical technique to locate catecholamines and 5-HT, I finally had a successful result, and the PhD that had seemed a remote possibility for many months finally began to look feasible. Given the enormously important topic of this volume – the discovery and development of drugs affecting 5-HT systems – this small excursion into Octopus neurochemistry might seem irrelevant. However, cephalopod molluscs have played important roles in the history of 5-HT. More than 30000 pairs of posterior salivary glands of Octopus vulgaris were used by Vittorio Erspamer, for the first extraction and identification of enteramine, which was later shown to be identical to serotonin discovered by John Gaddum, and chemically characterized as 5-hydroxytryptamine. Other molluscs have provided some of the most sensitive bioassays for 5-HT, as Gaddum and Paasonen described in 1955, and several participants in this Witness Seminar recollected either using such bioassays or investigating invertebrate pharmacology at the beginning of their careers. Many reflected, however, that invertebrate receptors seemed to be very different from those found in mammals; they had, as David Wallis put it, ‘a parallel pharmacology’. One Witness, Merton Sandler, remembered attending a lecture by Vittorio Erspamer in London in the early 1950s, and being intrigued enough to start work on the degradative enzyme monoamine oxidase, a field which became highly significant for the development of a whole class of therapeutic drugs: the monoamine oxidase inhibitor

Sodium leak through K2P potassium channels and cardiac arrhythmia, an emerging theme.

In this issue of EMBO Molecular Medicine, Decher et al (2017) identify a point mutation in the K2P2 (TREK‐1) potassium (K+) channel that changes function in just those ways expected to predispose to right ventricular outflow tract (RVOT) ventricular tachycardia (VT) in the patient they study. Whereas wild‐type channels are selective for K+ and inhibited by β‐adrenergic stimulation, mutant I267T channels pass sodium (Na+) into the cells, even during β‐adrenergic stimulation, and are more active in response to membrane stretch, changes predicted to enhance cardiac myocyte excitability. The report contributes to accumulating evidence for Na+ leak via K2P channels in association with normal development (Thomas et al, 2008), acquired arrhythmia (Ma et al, 2011), and now a missense mutation. Decher et al (2017) both inform and direct us toward interesting opportunities for further investigation