Acta Physiologica

Adult stem cells are crucial for normal tissue homeostasis and regeneration upon damage. Deregulated stem cell proliferation and/or differentiation have been linked to the formation and progression of tumours. Due to its high regenerative potential, the adult intestinal epithelium is an excellent system to study the mechanisms that underpin regeneration and transformation. Since the discovery of stem cell markers in the mammalian intestine – such as Lgr5 – and the presence of Drosophila intestinal stem cells there have been field‐changing discoveries that have revolutionized our understanding of intestinal homeostasis, stem cells and transformation. We will thus present a brief overview of these advances with an emphasis on the role of canonical Wnt signalling and the lessons learned from genetic tractable model systems.

This review attempts to touch on the history and application of amperometry at PC12 cells for fundamental investigation into the exocytosis process. PC12 cells have been widely used as a model for neural differentiation and as such they have been used to examine the effects of differentiation on exocytotic release and specifically release at varicosities. In addition, dexamethasone‐differentiated cells have been shown to have an increased number of releasable vesicles with increased quantal size, thereby allowing for an even broader range of applications including neuropharmacological and neurotoxicological studies. PC12 cells exhibiting large numbers of events have two distinct pools of vesicles, one about twice the quantal size of the other and each about half the total releasable vesicles. As will be outlined in this review, these cells have served as an extremely useful model of exocytosis in the study of the latency of stimulation‐release coupling, the role of exocytotic proteins in regulation of release, effect of drugs on quantal size, autoreceptors, fusion pore biophysics, environmental factors, health and disease. As PC12 cells have some advantages over other models for neurosecretion, including chromaffin cells, it is more than likely that in the following decade PC12 cells will continue to serve as a model to study exocytosis.

The regulation of volume is fundamental to life. There exist numerous conditions that can produce perturbations of cell volume. The cell has developed mechanisms to directly counteract these perturbations so as to maintain its physiological volume. Directed influx of the major extracellular cation, sodium, serves to counteract a decreased cell volume through the subsequent osmotically coupled movement of water to the intracellular space. This process, termed regulatory volume increase is often mediated by the ubiquitous sodium/hydrogen ion exchanger, NHE1. Similarly, the maintenance of intravascular volume is essential for the maintenance of blood pressure and consequently the proper perfusion of vital organs. Numerous mechanisms exist to counterbalance alterations in intravascular volume, not the least of which is the renal absorption of sodium filtered at the glomerulus. Two‐thirds of filtered sodium and water are absorbed in the renal proximal tubule, a mechanism that intimately involves the apical sodium/hydrogen ion exchanger, NHE3. This isoform is fundamental to the maintenance and regulation of intravascular volume and blood pressure. In this article, the effects of cell volume on the activity of these different isoforms, NHE1 and NHE3, will be described and the consequences of their activity on intracellular and intravascular volume will be explored.

Cardiomyocytes are highly coordinated cells with multiple proteins organized in micro domains. Minor changes or interference in subcellular proteins can cause major disturbances in physiology. The cardiac sodium channel (Na_V1.5) is an important determinant of correct electrical activity in cardiomyocytes which are localized at intercalated discs, T‐tubules and lateral membranes in the form of a macromolecular complex with multiple interacting protein partners. The channel is tightly regulated by post‐translational modifications for smooth conduction and propagation of action potentials. Among regulatory mechanisms, phosphorylation is an enzymatic and reversible process which modulates Na_V1.5 channel function by attaching phosphate groups to serine, threonine or tyrosine residues. Phosphorylation of Na_V1.5 is implicated in both normal physiological and pathological processes and is carried out by multiple kinases. In this review, we discuss and summarize recent literature about the (a) structure of Na_V1.5 channel, (b) formation and subcellular localization of Na_V1.5 channel macromolecular complex, (c) post‐translational phosphorylation and regulation of Na_V1.5 channel, and (d) how these phosphorylation events of Na_V1.5 channel alter the biophysical properties and affect the channel during disease status. We expect, by reviewing these aspects will greatly improve our understanding of Na_V1.5 channel biology, physiology and pathology, which will also provide an insight into the mechanism of arrythmogenesis at molecular level.

Nitric oxide (NO), a highly reactive gasotransmitter, is critical for a number of cellular processes and has multiple biological functions. Due to its limited lifetime and diffusion distance, NO has been mainly believed to act in autocrine/paracrine fashion. The increasingly recognized effects of pharmacologically delivered and endogenous NO at a distant site have changed the conventional wisdom and introduced NO as an endocrine signalling molecule. The notion is greatly supported by the detection of a number of NO adducts and their circulatory cycles, which in turn contribute to the transport and delivery of NO bioactivity, remote from the sites of its synthesis. The existence of endocrine sites of synthesis, negative feedback regulation of biosynthesis, integrated storage and transport systems, having an exclusive receptor, that is, soluble guanylyl cyclase (sGC), and organized circadian rhythmicity make NO something beyond a simple autocrine/paracrine signalling molecule that could qualify for being an endocrine signalling molecule. Here, we discuss hormonal features of NO from the classical endocrine point of view and review available knowledge supporting NO as a true endocrine hormone. This new insight can provide a new framework within which to reinterpret NO biology and its clinical applications.

Hypoxia is a consequence of inadequate oxygen availability. At the cellular level, lowered oxygen concentration activates signal cascades including numerous receptors, ion channels, second messengers, as well as several protein kinases and phosphatases. This, in turn, activates trans‐factors like transcription factors, RNA‐binding proteins and miRNAs, mediating an alteration in gene expression control. Each cell type has its unique constellation of oxygen sensors, couplers and effectors that determine the activation and predominance of several independent hypoxia‐sensitive pathways. Hence, altered gene expression patterns in hypoxia result from a complex regulatory network with multiple divergences and convergences. Although hundreds of genes are activated by transcriptional control in hypoxia, metabolic rate depression, as a consequence of reduced ATP level, causes inhibition of mRNA translation. In a multi‐phase response to hypoxia, global protein synthesis is suppressed, mainly by phosphorylation of eIF2‐alpha by PERK and inhibition of mTOR, causing suppression of 5′‐cap‐dependent mRNA translation. Growing evidence suggests that mRNAs undergo sorting at stress granules, which determines the fate of mRNA as to whether being translated, stored, or degraded. Data indicate that translation is suppressed only at ‘free’ polysomes, but is active at subsets of membrane‐bound ribosomes. The recruitment of specific mRNAs into subcellular compartments seems to be crucial for local mRNA translation in prolonged hypoxia. Furthermore, ribosomes themselves may play a significant role in targeting mRNAs for translation. This review summarizes the multiple facets of the cellular adaptation to hypoxia observed in mammals.