European Journal of Pharmacology (v.739, #C)

Calcium signalling and calcium channels: Evolution and general principles by Alexei Verkhratsky; Vladimir Parpura (1-3).
Calcium as a divalent cation was selected early in evolution as a signaling molecule to be used by both prokaryotes and eukaryotes. Its low cytosolic concentration likely reflects the initial concentration of this ion in the primordial soup/ocean as unicellular organisms were formed. As the concentration of calcium in the ocean subsequently increased, so did the diversity of homeostatic molecules handling calcium. This includes the plasma membrane channels that allowed the calcium entry, as well as extrusion mechanisms, i.e., exchangers and pumps. Further diversification occurred with the evolution of intracellular organelles, in particular the endoplasmic reticulum and mitochondria, which also contain channels, exchanger(s) and pumps to handle the homeostasis of calcium ions. Calcium signalling system, based around coordinated interactions of the above molecular entities, can be activated by the opening of voltage-gated channels, neurotransmitters, second messengers and/or mechanical stimulation, and as such is all-pervading pathway in physiology and pathophysiology of organisms.
Keywords: Calcium; Evolution; Prokaryotes; Eukaryotes; Channels; Transporters;

Intracellular calcium channels in protozoa by Roberto Docampo; Silvia N.J. Moreno; Helmut Plattner (4-18).
Ca2+-signaling pathways and intracellular Ca2+ channels are present in protozoa. Ancient origin of inositol 1,4,5-trisphosphate receptors (IP3Rs) and other intracellular channels predates the divergence of animals and fungi as evidenced by their presence in the choanoflagellate Monosiga brevicollis, the closest known relative to metazoans. The first protozoan IP3R cloned, from the ciliate Paramecium, displays strong sequence similarity to the rat type 3 IP3R. This ciliate has a large number of IP3- and ryanodine(Ry)-like receptors in six subfamilies suggesting the evolutionary adaptation to local requirements for an expanding diversification of vesicle trafficking. IP3Rs have also been functionally characterized in trypanosomatids, where they are essential for growth, differentiation, and establishment of infection. The presence of the mitochondrial calcium uniporter (MCU) in a number of protozoa indicates that mitochondrial regulation of Ca2+ signaling is also an early appearance in evolution, and contributed to the discovery of the molecular nature of this channel in mammalian cells. There is only sequence evidence for the occurrence of two-pore channels (TPCs), transient receptor potential Ca2+ channels (TRPCs) and intracellular mechanosensitive Ca2+-channels in Paramecium and in parasitic protozoa.
Keywords: Calcium channels; Protozoa; Paramecium; Toxoplasma; Trypanosoma; Mitochondrial calcium uniporter;

Calcium channels, external calcium concentration and cell proliferation by Anne-Sophie Borowiec; Gabriel Bidaux; Natascha Pigat; Vincent Goffin; Sophie Bernichtein; Thierry Capiod (19-25).
Evidence for a role for calcium channel proteins in cell proliferation is numerous suggesting that calcium influx is essential in this physiological process. Several studies in the past thirty years have demonstrated that calcium channel expression levels are determinant in cell proliferation. Voltage-gated, store-operated, second messengers and receptor-operated calcium channels have been associated to cell proliferation. However, the relationship between calcium influx and cell proliferation can be uncoupled in transformed and cancer cells, resulting in an external calcium-independent proliferation. Thus, protein expression could be more important than channel function to trigger cell proliferation suggesting that additional channel functions may be responsible to reconcile calcium channel expression and cell proliferation. When needed, external calcium concentration is obviously important for calcium channel function but it also regulates calcium sensing receptor (CaSR) activity. CaSR can up- or down-regulate cell proliferation depending on physiological conditions. CaSR sensitivity to external calcium is within the 0.5 to 5 mM range and therefore, the role of these receptors in cell proliferation must be taken into account. We therefore suggest here that cell proliferation rates could depend on the relative balance between calcium influx and CaSR activation.
Keywords: Calcium channels; Cell cycle; Cell proliferation; Calcium sensing receptor;

Ryanodine receptors as leak channels by Agustín Guerrero-Hernández; Guillermo Ávila; Angélica Rueda (26-38).
Ryanodine receptors are Ca2+ release channels of internal stores. This review focuses on those situations and conditions that transform RyRs from a finely regulated ion channel to an unregulated Ca2+ leak channel and the pathological consequences of this alteration. In skeletal muscle, mutations in either CaV1.1 channel or RyR1 results in a leaky behavior of the latter. In heart cells, RyR2 functions normally as a Ca2+ leak channel during diastole within certain limits, the enhancement of this activity leads to arrhythmogenic situations that are tackled with different pharmacological strategies. In smooth muscle, RyRs are involved more in reducing excitability than in stimulating contraction so the leak activity of RyRs in the form of Ca2+ sparks, locally activates Ca2+-dependent potassium channels to reduce excitability. In neurons the enhanced activity of RyRs is associated with the development of different neurodegenerative disorders such as Alzheimer and Huntington diseases. It appears then that the activity of RyRs as leak channels can have both physiological and pathological consequences depending on the cell type and the metabolic condition.
Keywords: Ryanodine receptors; Leak channels; Skeletal muscle; Heart muscle; Smooth muscle; Neurons;

Intracellular calcium channels: Inositol-1,4,5-trisphosphate receptors by Olena A. Fedorenko; Elena Popugaeva; Masahiro Enomoto; Peter B. Stathopulos; Mitsuhiko Ikura; Ilya Bezprozvanny (39-48).
The inositol-1,4,5-trisphosphate receptors (InsP3Rs) are the major intracellular Ca2+-release channels in cells. Activity of InsP3Rs is essential for elementary and global Ca2+ events in the cell. There are three InsP3Rs isoforms that are present in mammalian cells. In this review we will focus primarily on InsP3R type 1. The InsP3R1 is a predominant isoform in neurons and it is the most extensively studied isoform. Combination of biophysical and structural methods revealed key mechanisms of InsP3R function and modulation. Cell biological and biochemical studies lead to identification of a large number of InsP3R-binding proteins. InsP3Rs are involved in the regulation of numerous physiological processes, including learning and memory, proliferation, differentiation, development and cell death. Malfunction of InsP3R1 play a role in a number of neurodegenerative disorders and other disease states. InsP3Rs represent a potentially valuable drug target for treatment of these disorders and for modulating activity of neurons and other cells. Future studies will provide better understanding of physiological functions of InsP3Rs in health and disease.
Keywords: Inositol 1,4,5-trisphosphate receptors; Cell nucleus; Ca2+ signaling; Neurodegeneration;

How ORAI and TRP channels interfere with each other: Interaction models and examples from the immune system and the skin by Stephanie Saul; Hedwig Stanisz; Christian S. Backes; Eva C. Schwarz; Markus Hoth (49-59).
Four types of Ca2+ selective ion channels are known, ten voltage gated Ca2+ (CaV) channels, four CatSper channels, three store operated CRAC channels (ORAI channels) and at least two members of the TRPV subfamily (TRPV5, TRPV6). Some of the other TRP channels also show some Ca2+ selectivity like certain splice variants of TRPM3. In addition to Ca2+ selective channels, various cation channels play an important role for Ca2+ entry and furthermore, they may also regulate Ca2+ entry through other channels by modulating the membrane potential or other means as outlined in this review. Of the different types of cation channels, TRP channels form one of the most prominent families of non-selective cation channels with functional relevance in electrically non-excitable and electrically excitable cell types. Among these, the seven channels of the TRPC subfamily are rather non-selective with very modest Ca2+ selectivity, whereas in the other subfamilies, cation selectivity ranges from monovalent selectivity (i.e. TRPM4, TRPM5) to divalent selectivity (i.e. TRPM6, TRPM7) or Ca2+ selectivity (i.e. TRPV5, TRPV6). Rather than discussing the heavily reviewed individual functions of ORAI or TRP channels, we summarize data and present models how TRP and ORAI may functionally interact to guide cellular functions. We focus on T lymphocytes representing a more ORAI-dominated tissue and skin as model system in which both ORAI and TRP channel have been reported to control relevant functions. We present several interaction models how ORAI and TRP may interfere with each other's function.
Keywords: ORAI1; STIM1; TRPC; T lymphocytes; keratinocytes; Melanocytes;

Calcium permeability of ligand-gated Ca2+ channels by Yuriy Pankratov; Ulyana Lalo (60-73).
Many of cation-permeable ionotropic receptors to various neurotransmitters, such as glutamate, acetylcholine and ATP, are permeable to Ca2+ ions. For some of them, in particular NMDA, nicotinic Ach and P2X receptors, permeability to Ca2+ is higher than permeability to monovalent cations. Such receptors can be viewed as ligand-gated Ca2+-channels (LGCCs). This review provides an overview of past works on structure LGCCs, including structural motifs responsible for their interaction with Ca2+ ions, and functional implications of their Ca2+-permeability. The NMDA, P2X and nicotinic Ach receptors are abundantly expressed in the central nervous system. They are present at the nerve terminals, postsynaptic, extrasynaptic and glial membrane and therefore can contribute to synaptic function at different levels. Their heteromeric structure leads to wide variety of LGCC subtypes and great diversity of their functional properties. The influx of Ca2+ provided by LGCCs can activate a plethora of secondary messenger cascades, which can modulate activity, trafficking and lateral mobility of LGCCs and thereby are entangled with their physiological function. In the discussion of the physiological importance of LGCCs we are focusing on emerging evidence on their role in control of synaptic transmission, plasticity and glia–neuron interaction.
Keywords: NMDA receptor; GluN3 subunit; Nicotinic receptor; P2X receptor; Synaptic plasticity; Trafficking; Calcium permeability; Ca2+-signalling; Glia–neuron interaction; Presynaptic receptor; Neurotransmitter release; Calmodulin; CaMKII; PKC; VILIP1; Lateral diffusion;

FK506-binding protein 1b/12.6: A key to aging-related hippocampal Ca2+ dysregulation? by J.C. Gant; E.M. Blalock; K-.C. Chen; I. Kadish; N.M. Porter; C.M. Norris; O. Thibault; P.W. Landfield (74-82).
It has been recognized for some time that the Ca2+-dependent slow afterhyperpolarization (sAHP) is larger in hippocampal neurons of aged compared with young animals. In addition, extensive studies since have shown that other Ca2+-mediated electrophysiological responses are increased in hippocampus with aging, including Ca2+ transients, L-type voltage-gated Ca2+ channel activity, Ca2+ spike duration and action potential accommodation. Elevated Ca2+-induced Ca2+ release from ryanodine receptors (RyRs) appears to drive amplification of the Ca2+ responses. Components of this Ca2+ dysregulation phenotype correlate with deficits in cognitive function and plasticity, indicating they may play critical roles in aging-related impairment of brain function. However, the molecular mechanisms underlying aging-related Ca2+ dysregulation are not well understood. FK506-binding proteins 1a and 1b (FKBP1a/1b, also known as FKBP12/12.6) are immunophilin proteins that bind the immunosuppressant drugs FK506 and rapamycin. In muscle cells, FKBP1a/1b also bind RyRs and inhibits Ca2+-induced Ca2+ release, but it is not clear whether FKBPs act similarly in brain cells. Recently, we found that selectively disrupting hippocampal FKBP1b function in young rats, either by microinjecting adeno-associated viral vectors expressing siRNA, or by treatment with rapamycin, increases the sAHP and recapitulates much of the hippocampal Ca2+ dysregulation phenotype. Moreover, in microarray studies, we found FKBP1b gene expression was downregulated in hippocampus of aging rats and early-stage Alzheimer's disease subjects. These results suggest the novel hypothesis that declining FKBP function is a key factor in aging-related Ca2+ dysregulation in the brain and point to potential new therapeutic targets for counteracting unhealthy brain aging.
Keywords: Calcium; Ryanodine receptor; Aging; FKBP1b;

Calcium ions are versatile and universal biological signaling factors that regulate numerous cellular processes ranging from cell fertilization, to neuronal plasticity that underlies learning and memory, to cell death. For these functions to be properly executed, calcium signaling requires precise regulation, and failure of this regulation may tip the scales from a signal for life to a signal for death. Disruptions in calcium channel function can generate complex multi-system disorders collectively referred to as “calciumopathies” that can target essentially any cell type or organ. In this review, we focus on the multifaceted involvement of calcium signaling in the pathophysiology of Alzheimer's disease (AD), and summarize the various therapeutic options currently available to combat this disease. Detailing the series of disappointing AD clinical trial results on cognitive outcomes, we emphasize the urgency to design alternative therapeutic strategies if synaptic and memory functions are to be preserved. One such approach is to target early calcium channelopathies centrally linked to AD pathogenesis.
Keywords: Ryanodine receptor; IP3R; ER; Neuron; Brain; Neurodegeneration; Calcium; Alzheimer's disease; Synaptic plasticity; Amyloid; Clinical trials;

Several factors besides high intraocular pressure assumed to be associated with the development and progression of glaucoma, and calcium channel blockers (CCBs) have been an anticipated option for glaucoma treatment by improving ocular perfusion and/or exerting neuroprotective effects on retinal ganglion cells with safety established in wide and long-term usage. Decrease in IOP has been reported after topical application of CCBs, however, the effect is much smaller and almost negligible after systemic application. Various CCBs have been reported to increase posterior ocular blood flow in vivo and to exert direct neuroprotection in neurons in vitro. Distribution of the drug at a pharmacologically active concentration in the posterior ocular tissues across the blood–brain barrier or blood–retina barrier, especially in the optic nerve head and retina where the ganglion cells mainly suffer from glaucomatous damage, is essential for clinical treatment of glaucoma. Improved visual functions such as sensitivity in the visual field test have been reported after administration of CCBs, but evidences from the randomized studies have been limited and effects of CCBs on blood flow and direct neuroprotection are hardly distinguished from each other.
Keywords: Glaucoma; Intraocular pressure; Blood flow; Neuroprotection; Calcium channel blocker; Visual field;