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Abstract: Canonical transient receptor potential 1 (TRPC1) plasmalemmal cation channels mediate Ca2+ and Na+ fluxes and control respective cytoplasmic ion signals in rat cortical astrocytes. Mechanical stimulation of astrocytes results in an increase in the levels of cytosolic Ca2+ and Na+ that are in part due to entry of extracellular cations through TRPC1 containing channels. Inhibition of the TRPC1 pore with an antibody against its selective filter reduced cytosolic Ca2+ accumulation caused by mechanical stimulation. In contrast, this immunological treatment increased the cytosolic Na+ peak accumulation induced by mechanical stimulation. We propose that TRPC channels are amenable to changes in selective filtering, as mutations in previous studies and antibody binding in our present study differentially affect the flux of Ca2+ and Na+. TRPC1 containing channels might represent focal points for co-ordination of Ca2+ and Na+ signalling in astroglia and this can have consequences on Ca2+- and Na+-dependent processes such as regulated exocytosis and lactate production, respectively, which in turn can modulate neuronal synaptic transmission. [Copyright &y& Elsevier]

Abstract: Multiple mechanisms that maintain Ca2+ homeostasis and provide for Ca2+ signalling operate in the somatas and neurohypophysial nerve terminals of supraoptic nucleus (SON) neurones. Here, we examined the Ca2+ clearance mechanisms of SON neurones from adult rats by monitoring the effects of the selective inhibition of different Ca2+ homeostatic molecules on cytosolic Ca2+ ([Ca2+]i) transients in isolated SON neurones. In addition, we measured somatodendritic vasopressin (AVP) release from intact SON tissue in an attempt to correlate it with [Ca2+]i dynamics. When bathing the cells in a Na+-free extracellular solution, thapsigargin, cyclopiazonic acid (CPA), carbonyl cyanide 3-chlorophenylhydrazone (CCCP), and the inhibitor of plasma membrane Ca2+-ATPase (PMCA), La3+, all significantly slowed down the recovery of depolarisation (50mM KCl)-induced [Ca2+]i transients. The release of AVP was stimulated by 50mM KCl, and the decline in the peptide release was slowed by Ca2+ transport inhibitors. In contrast to previous reports, our results show that in the fully mature adult rats: (i) all four Ca2+ homeostatic pathways, the Na+/Ca2+ exchanger, the endoplasmic reticulum Ca2+ pump, the plasmalemmal Ca2+ pump and mitochondria, are complementary in actively clearing Ca2+ from SON neurones; (ii) somatodendritic AVP release closely correlates with intracellular [Ca2+]i dynamics; (iii) there is (are) Ca2+ clearance mechanism(s) distinct from the four outlined above; and (iv) Ca2+ homeostatic systems in the somatas of SON neurones differ from those expressed in their terminals. [ABSTRACT FROM AUTHOR]

Abstract: Local, global and propagating calcium (Ca2+) signals provide the substrate for glial excitability. Here we analyse Ca2+ permeability of NMDA and P2X1/5 receptors expressed in cortical astrocytes and provide evidence that activation of these receptors trigger astroglial Ca2+ signals when stimulated by either endogenous agonists or by synaptic release of neurotransmitters. The Ca2+ permeability of the ionotropic receptors was determined by reversal potential shift analysis; the permeability ratio P Ca/P K was 3.1 for NMDA receptors and 2.2 for P2X1/5 receptors. Selective stimulation of ionotropic receptors (with NMDA and α,β-methyleneATP) in freshly isolated cortical astrocytes induced ion currents associated with transient increases in cytosolic Ca2+ concentration ([Ca2+]i). Stimulation of neuronal afferents in cortical slices triggered glial synaptic currents and [Ca2+]i responses, which were partially blocked by selective antagonists of NMDA (D-AP5 and UBP141) and P2X1/5 (NF449) receptors. We conclude that ionotropic receptors contribute to astroglial Ca2+ signalling and may provide a specific mechanism for fast neuronal–glial signalling at the synaptic level. [ABSTRACT FROM AUTHOR]

Abstract: Simultaneous recording of cytosolic and sarco-endoplasmic reticulum (SR/ER) luminal free calcium concentrations ([Ca2+] i and [Ca2+]L, respectively) supports the notion that release channels (RyRs and IP3Rs) use a concealed Ca2+ source, likely to be associated with intra-SR/ER Ca2+ binding proteins, whereas SR/ER Ca2+ leak channels can only access free luminal Ca2+. We hypothesize that Ca2+ is trapped by oligomers of luminal Ca2+-binding proteins and that the opening of release channels induces the rapid liberation of this “concealed” Ca2+ source associated with intra-ER Ca2+ buffers. Our hypothesis may also clarify why SERCA pumps potentiate Ca2+ release and explain quantal characteristics and refractory states of Ca2+ release process. [ABSTRACT FROM AUTHOR]

Summary: The World Health Organization (WHO) predicts there will be 300 million people world-wide with diabetes mellitus by 2025. Currently it is estimated that there are 20 and 60 million people suffering from diabetes mellitus in North America and Europe, respectively. Within this huge population of diabetic persons approximately 50% will develop some form of sensory polyneuropathy, which involves the dying back of distal axons and a failure of axons to regenerate. This leads to incapacitating pain, sensory loss and poor wound healing. The end result is lower extremity amputation with approximately 90,000 diabetes-related amputations occurring each year in North America and the expectation of a 5-fold increase over the next 10 years due to increased incidence of type 2 diabetes. Abnormal neuronal Ca2+ homeostasis and impaired mitochondrial function have been implicated in numerous CNS and PNS diseases including diabetic sensory neuropathy. The endoplasmic reticulum (ER), in part, regulates cellular Ca2+ homeostasis and this process is linked to regulation of mitochondrial function and activity of anti-apoptotic signal transduction pathways. Here we review the current state of research regarding role of Ca2+ dyshomeostasis and mitochondrial physiology in neuronal dysfunction in diabetes. The central impact of diabetes-induced alteration of Ca2+ handling on sensory neurone function is discussed and related to abnormal ER performance. New results are presented showing suboptimal Ca2+ concentration in the ER lumen in association with reduced SERCA2 expression in sensory neurones from type 1 diabetic rats. We hypothesize that deficits in neurotrophic factor support, specifically linked to diabetes-induced lowered expression of insulin and neurotrophin-3, triggers alterations of sensory neurone phenotype that are critical for the development of abnormal Ca2+ homeostasis and associated mitochondrial dysfunction. The role of hyperglycaemia in diabetes is also discussed and we propose that high glucose concentration may impact at other sites to contribute to the heterogeneous aetiology of nerve damage in diabetes. [Copyright &y& Elsevier]

Abstract: One of the most crucial aspects of Ca2+ signalling is the ability to generate highly localised transient elevations of the cytosolic Ca2+ concentration at specific strategically important target sites. Inevitably this necessitates a relatively high Ca2+ buffering power of the cytoplasm, which in turn makes movement of Ca2+ from one part of a cell to another difficult. Nature has evolved an elegant solution to this problem by creating operational Ca2+ tunnels through the endoplasmic reticulum. Very recently direct evidence that such tunnelling also occurs in neurons has been provided. [Copyright &y& Elsevier]

Abstract: Specific Ca2+ homeostatic system appeared very early in the history of the cell, as a survival system preventing Ca2+-mediated cell damage. This homeostatic system produced a steep (∼20,000 times) concentration gradient between extracellular and intracellular compartments, which has both survival importance (even relatively short increases in cytosolic Ca2+ concentrations higher then 100nM are incompatible with life) and signalling function. Evolution utilised this gradient together with an ability of Ca2+ to interact with many biological molecules to create the most widespread and versatile signalling system, controlling the majority of cellular processes and executing complex routines of intercellular communications. [Copyright &y& Elsevier]

Abstract: T-type, or low-voltage-activated (LVA), tiny and transient Ca2+ currents pare more and more recognised as universal players in a plethora of cell functions and are also more and more connected to several diseases. This short introduction reviews the discovery of T-type Ca2+ channels, describes its basic properties and sketches its cloning and physiological impact. Finally, an overview is given how research on T-type Ca2+ channels has developed in the last years and in which topics it is branching out, a process, which is still ongoing. [Copyright &y& Elsevier]