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PubMed2006

LPA(4)/GPR23 is a lysophosphatidic acid (LPA) receptor utilizing G(s)-, G(q)/G(i)-mediated calcium signaling and G(12/13)-mediated Rho activation.

Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that signals through G protein-coupled receptors (GPCRs) to produce a range of biological responses. A recently reported fourth receptor, LPA(4)/GPR23, was notable for its low homology to the previously identified receptors LPA(1-3) and for its ability to increase intracellular concentrations of cAMP and calcium. However, the signaling pathways leading to LPA(4)-mediated induction of cAMP and calcium levels have not been reported. Using epitope-tagged LPA(4), pharmacological intervention, and G protein mini-genes, we provide independent confirmatory evidence that supports LPA(4) as a fourth LPA receptor, including LPA concentration-dependent responses and specific membrane binding. Importantly, we further demonstrate new LPA-dependent activities of LPA(4) that include the following: receptor internalization; G(12/13)- and Rho-mediated neurite retraction and stress fiber formation; G(q) protein and pertussis toxin-sensitive calcium mobilization and activation of a nonselective cation conductance; and cAMP increases mediated by G(s). The receptor is broadly expressed in embryonic tissues, including brain, as determined by Northern blot and reverse transcription-PCR analysis. Adult tissues have increased expression in skin, heart, and to a lesser extent, thymus. These data confirm the identification and extend the functionality of LPA(4) as an LPA receptor, bringing the number of independently verified LPA receptors to five, with both overlapping and distinct signaling properties and tissue expression.

Adult↗
PubMed2006

Thirty years of calcium signals at fertilization.

It was discovered about 30 years ago that a dramatic increase in intracellular calcium ion concentration ([Ca(2+)](i)) occurs at fertilization and that this increase acts as the pivotal signal for egg activation. Later, the Ca(2+) signal at fertilization turned out to be ubiquitous among animal species. Extensive advance has been brought during these 30 years in research on spatiotemporal aspects and signaling mechanisms of the [Ca(2+)](i) increase, sperm factors that induce the Ca(2+) response, and cell cycle resumption caused by the [Ca(2+)](i) rise. I provide a historical account of these advances in mammals, sea urchins, and a few other models.

Animals↗
PubMed2002

Spike timing, calcium signals and synaptic plasticity.

Plasticity at central synapses depends critically on the timing of presynaptic and postsynaptic action potentials. Key initial steps in synaptic plasticity involve the back-propagation of action potentials into the dendritic tree and calcium influx that depends nonlinearly on the action potential and synaptic input. These initial steps are now better understood. In addition, recent studies of processes as diverse as gene expression and channel inactivation suggest that responses to calcium transients depend not only their amplitude, but on their time course and on the location of their origin.

Action Potentials↗
PubMed1999

Effect of amlodipine therapy on the monoclonal antibody 3G8-induced calcium signal in polymorphonuclear leukocytes of hemodialysis patients.

Chronic renal failure is associated with impaired phagocytosis. This was attributed to the PTH-induced elevation of basal levels of [Ca2+]i of polymorphonuclear leukocytes (PMNLs) and to the small calcium transient induced by the ligation of the Fcgamma RIII receptors of these cells with 3G8 monoclonal antibodies. The blocking of the action of PTH on the PMNLs of patients with chronic renal failure by their treatment with a calcium channel blocker normalized the basal levels of [Ca2+]i of the PMNLs and reversed the defect in their phagocytic property. It is not known whether such therapy would also restore the calcium transient in the PMNLs in response to 3G8 monoclonal antibody to normal. We examined this issue in 12 normal subjects and 18 hemodialysis patients; 9 of them were treated with the calcium channel blocker, amlodipine, and the other 9 did not receive such therapy. The treatment with amlodipine normalized [Ca2+]i of PMNLs as well as the calcium transient in response to 3G8 monoclonal antibody and reversed the defect in their phagocytosis. It is concluded that chronic renal failure is associated with deranged calcium homeostasis of PMNLs which causes abnormalities in the function of Fcgamma RIII receptors and consequently results in impaired phagocytosis. Therapy with a calcium channel blocker can reverse all these derangements in metabolism and function of PMNLs.

Adult↗
PubMed2001

Calcium signalling in cells of oligodendroglial lineage.

Intracellular Ca2+ is the key signal that regulates the efficacy of neurotransmitter release and synaptic plasticity in neurons but is also an important second messenger involved in the signal transduction and modulation of gene expression in both excitable and non-excitable cells. Glial cells, including cells of oligodendroglial (OLG) lineage, are capable of responding to extracellular stimuli via changes in the intracellular Ca2+. This review article focuses on the mechanisms of Ca2+ signalling in cells of OLG lineage with the goal of providing the basis for understanding the relevance of receptor- and non-receptor-mediated signalling to oligodendroglial development, myelination, and demyelination. Conclusions to date indicate that cells of OLG lineage exhibit remarkable plasticity with regard to the expression of ion channels and receptors linked to Ca2+ signalling and that perturbation of [Ca2](i) homeostasis contributes to the pathogenesis of demyelinating diseases.

Animals↗
PubMed2001

Participation of mitochondria in calcium signalling in the exocrine pancreas.

This minireview is an attempt to put together some of the recent advances regarding the implications of mitochondria in Ca2+ homeostasis. Although the main role of this cytoplasmic organelle is ATP supply to the cell, during the past years strong evidence has been accumulated supporting an active role of these organelles in Ca2+ handling by the cell. The discovery of mitochondrial specific fluorescent dyes has permitted the study of these organelles within living cells. Due to its ubiquitous localisation within the cytosol, mitochondria would play an important role in the modulation of the subcellular patterns of Ca2+ signalling, and therefore would act as modulators of Ca2+-dependent cellular processes.

Animals↗
PubMed2004

Deranged neuronal calcium signaling and Huntington disease.

Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder that primarily affects medium spiny striatal neurons (MSN). HD is caused by polyglutamine (polyQ) expansion (exp) in the amino-terminal region of a protein huntingtin (Htt). The connection between polyQ expansion in Httexp and MSN neurodegeneration remains elusive. Here we discuss recent data that link polyQ expansion in Httexp and deranged Ca2+ signaling in MSN neurons. Experimental evidence indicates that (1) Ca2+ homeostasis is abnormal in mitochondria isolated from lymphoblasts of HD patients and from brains of the YAC72 HD mouse model; (2) Httexp leads to potentiation of NR1/NR2B NMDA receptor activity in heterologous expression systems and in MSN from YAC72 HD mouse model; and (3) Httexp binds to the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1) carboxy-terminus and causes sensitization of InsP3R1 to activation by InsP3 in planar lipid bilayers and in MSN. Based on these results we propose that Httexp-induced cytosolic and mitochondrial Ca2+ overload of MSN plays an important role in the pathogenesis of HD and that Ca2+ signaling blockers may play a beneficial role in treatment of HD.

Animals↗
PubMed2006

Potentiation of native and recombinant P2X7-mediated calcium signaling by arachidonic acid in cultured cortical astrocytes and human embryonic kidney 293 cells.

In the brain, arachidonic acid (AA) plays a critical role in the modulation of a broad spectrum of biological responses, including those underlying neuroinflammation. By using microfluorometry, we investigated the action of extracellular AA in the modulation of the purinoceptor P2X7-mediated elevation of [Ca(2+)](i) in cultured neocortical type-1 astrocytes and P2X7-, P2X2-transfected human embryonic kidney (HEK) 293 cells. We report that in cultured astrocytes, AA-induced [Ca(2+)](i) elevation is coupled to depletion of intracellular Ca(2+) stores and to a sustained noncapacitative Ca(2+) entry. AA also induced a robust potentiation of the astrocytic P2X7-mediated [Ca(2+)](i) rise evoked by the selective agonist 3'-O-(4-benzoyl)benzoyl-ATP (BzATP). Pharmacological studies demonstrate that the selective P2X7 antagonists oxidized ATP and Brilliant Blue G abrogated the AA-mediated potentiation of BzATP-evoked [Ca(2+)](i) elevation. Fluorescent dye uptake experiments showed that the AA-induced increase in [Ca(2+)](i) was not due to a switch of the P2X7 receptor from channel to the pore mode of gating. The synergistic effect of AA and BzATP was also observed in HEK293 cells stably expressing rat and human P2X7 but not in rat P2X2. Control HEK293 cells responded to AA exposure only with a transient [Ca(2+)](i) elevation, whereas in those expressing the P2X7 receptor, AA elicited a potentiation of the BzATP-induced [Ca(2+)](i) rise. Together, these findings indicate that AA mediates a complex regulation of [Ca(2+)](i) dynamics also through P2X7-mediated Ca(2+) entry, suggesting that variations in AA production may be relevant to the control of both the temporal and spatial kinetics of [Ca(2+)](i) signaling in astroglial cells.

Adenosine Triphosphate↗
PubMed1998

Phytohemagglutinin-stimulated calcium signal in lymphocytes of alcoholics before, during and after detoxification.

Acute and chronic exposure to ethanol influences intracellular calcium homeostasis via NMDA receptors, direct regulation of calcium channels or the phosphoinositide pathway. To explore the influence of alcohol withdrawal on calcium metabolism, we have investigated the resting and phytohemagglutinin (PHA) stimulated [Ca2+]i in lymphocytes of 10 alcoholics before, during and after withdrawal. Our findings suggest that both compartments of the PHA-stimulated signal are affected in alcoholics, with flattening of the initial peak and sustained calcium influx, as long as severe vegetative signs are present. MANOVA results showed significant interaction effects for both measurement points, for the initial peak, 40 s after stimulation (P = 0.05), and especially for the sustained influx at the end of the observation period (P = 0.001). The detailed mechanisms of this disturbed calcium homeostasis need further investigation.

Adult↗
PubMed2001

Calcium signaling pathways utilized by P2X receptors in freshly isolated preglomerular MVSMC.

This study tested the hypothesis that P2X receptor activation increases intracellular Ca(2+) concentration ([Ca(2+)](i)) in preglomerular microvascular smooth muscle cells (MVSMC) by evoking voltage-dependent calcium influx. MVSMC were obtained and loaded with the calcium-sensitive dye fura 2 and studied by using single-cell fluorescence microscopy. The effect of P2X receptor activation on [Ca(2+)](i) was assessed by using the P2X receptor-selective agonist alpha,beta-methylene-ATP and was compared with responses elicited by the endogenous P2 receptor agonist ATP. alpha,beta-Methylene-ATP increased [Ca(2+)](i) dose dependently. Peak increases in [Ca(2+)](i) averaged 37 +/- 11, 73 +/- 15, and 103 +/- 21 nM at agonist concentrations of 0.1, 1, and 10 microM, respectively. The average peak response elicited by 10 microM alpha,beta-methylene-ATP was approximately 34% of the response obtained with 10 microM ATP. alpha,beta-Methylene-ATP induced a transient increase in [Ca(2+)](i) before [Ca(2+)](i) returned to baseline, whereas ATP induced a biphasic response including a peak response followed by a sustained plateau. In Ca(2+)-free medium, ATP induced a sharp transient increase in [Ca(2+)](i), whereas the response to alpha,beta-methylene-ATP was abolished. Ca(2+) channel blockade with 10 microM diltiazem or nifedipine attenuated the response to alpha,beta-methylene-ATP, whereas nonspecific blockade of Ca(2+) influx pathways with 5 mM Ni(2+) abolished the response. Blockade of P2X receptors with the novel P2X receptor antagonist NF-279 completely but reversibly abolished the response to alpha,beta-methylene-ATP. These results indicate that P2X receptor activation by alpha,beta-methylene-ATP increases [Ca(2+)](i) in preglomerular MVSMC, in part, by stimulating voltage-dependent Ca(2+) influx through L-type Ca(2+) channels.

Adenosine Triphosphate↗
PubMed1999

Calcium signaling in the developing Xenopus myotome.

Embryonic Xenopus myocytes generate spontaneous calcium (Ca(2+)) transients during differentiation in culture. Suppression of these transients disrupts myofibril organization and the formation of sarcomeres through an identified signal transduction cascade. Since transients often occur during myocyte polarization and migration in culture, we hypothesized they might play additional roles in vivo during tissue formation. We have tested this hypothesis by examining Ca(2+) dynamics in the intact Xenopus paraxial mesoderm as it differentiates into the mature myotome. We find that Ca(2+) transients occur in cells of the developing myotome with characteristics remarkably similar to those in cultured myocytes. Transients produced within the myotome are correlated with somitogenesis as well as myocyte maturation. Since transients arise from intracellular stores in cultured myocytes, we examined the functional distribution of both IP(3) and ryanodine receptors in the intact myotome by eliciting Ca(2+) elevations in response to photorelease of caged IP(3) and superfusion of caffeine, respectively. As in culture, transients in vivo depend on Ca(2+) release from ryanodine receptor (RyR) stores, and blocking RyR during development interferes with somite maturation.

Animals↗
PubMed2003

Effects of insulin on luteinizing hormone and prolactin secretion and calcium signaling in female rat pituitary cells.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is associated with insulin resistance and hyperinsulinemia, which might contribute to the hypersecretion of luteinizing hormone (LH). Hyperprolactinemia is another finding in a subgroup of patients with PCOS, whereas its relation to hyperinsulinemia is not fully understood yet. METHODS: In the present study we tested the hypothesis that insulin might affect LH or prolactin secretion of cultured female rat pituitary cells. To address the mechanisms by which insulin could act at the intracellular level we examined the GnRH- and TRH-induced Ca(2+) signals in single gonadotrophs and lactotrophs, because Ca(2+) is an important component of GnRH signal transduction that is closely related to exocytosis. RESULTS: Cells treated for 24 h with insulin (10(-9) M) showed an enhancement of basal and agonist-induced LH and prolactin secretion. Insulin did not affect GnRH- and TRH-induced Ca(2+) signals compared to controls. There were no differences neither in the frequency nor in the amplitude of the Ca signal. CONCLUSION: Our findings suggest that insulin might contribute to LH hypersecretion. Insulin might be partially responsible for hyperprolactinemia. Since insulin did not affect Ca signaling, other components of the GnRH signal transduction pathway might be involved in LH hypersecretion.

Animals↗
PubMed2006

Dynamic inositol trisphosphate-mediated calcium signals within astrocytic endfeet underlie vasodilation of cerebral arterioles.

Active neurons communicate to intracerebral arterioles in part through an elevation of cytosolic Ca(2+) concentration ([Ca(2+)](i)) in astrocytes, leading to the generation of vasoactive signals involved in neurovascular coupling. In particular, [Ca(2+)](i) increases in astrocytic processes ("endfeet"), which encase cerebral arterioles, have been shown to result in vasodilation of arterioles in vivo. However, the spatial and temporal properties of endfoot [Ca(2+)](i) signals have not been characterized, and information regarding the mechanism by which these signals arise is lacking. [Ca(2+)](i) signaling in astrocytic endfeet was measured with high spatiotemporal resolution in cortical brain slices, using a fluorescent Ca(2+) indicator and confocal microscopy. Increases in endfoot [Ca(2+)](i) preceded vasodilation of arterioles within cortical slices, as detected by simultaneous measurement of endfoot [Ca(2+)](i) and vascular diameter. Neuronal activity-evoked elevation of endfoot [Ca(2+)](i) was reduced by inhibition of inositol 1,4,5-trisphosphate (InsP(3)) receptor Ca(2+) release channels and almost completely abolished by inhibition of endoplasmic reticulum Ca(2+) uptake. To probe the Ca(2+) release mechanisms present within endfeet, spatially restricted flash photolysis of caged InsP(3) was utilized to liberate InsP(3) directly within endfeet. This maneuver generated large amplitude [Ca(2+)](i) increases within endfeet that were spatially restricted to this region of the astrocyte. These InsP(3)-induced [Ca(2+)](i) increases were sensitive to depletion of the intracellular Ca(2+) store, but not to ryanodine, suggesting that Ca(2+)-induced Ca(2+) release from ryanodine receptors does not contribute to the generation of endfoot [Ca(2+)](i) signals. Neuronally evoked increases in astrocytic [Ca(2+)](i) propagated through perivascular astrocytic processes and endfeet as multiple, distinct [Ca(2+)](i) waves and exhibited a high degree of spatial heterogeneity. Regenerative Ca(2+) release processes within the endfeet were evident, as were localized regions of Ca(2+) release, and treatment of slices with the vasoactive neuropeptides somatostatin and vasoactive intestinal peptide was capable of inducing endfoot [Ca(2+)](i) increases, suggesting the potential for signaling between local interneurons and astrocytic endfeet in the cortex. Furthermore, photorelease of InsP(3) within individual endfeet resulted in a local vasodilation of adjacent arterioles, supporting the concept that astrocytic endfeet function as local "vasoregulatory units" by translating information from active neurons into complex InsP(3)-mediated Ca(2+) release signals that modulate arteriolar diameter.

Animals↗
PubMed2001

The versatility and complexity of calcium signalling.

Ca2+ is a universal second messenger used to regulate a wide range of cellular processes such as fertilization, proliferation, contraction, secretion, learning and memory. Cells derive signal Ca2+ from both internal and external sources. The Ca2+ flowing through these channels constitute the elementary events of Ca2+ signalling. Ca2+ can act within milliseconds in highly localized regions or it can act much more slowly as a global wave that spreads the signal throughout the cell. Various pumps and exchangers are responsible for returning the elevated levels of Ca2+ back to the resting state. The mitochondrion also plays a critical role in that it helps the recovery process by taking Ca2+ up from the cytoplasm. Alterations in the ebb and flow of Ca2+ through the mitochondria can lead to cell death. A good example of the complexity of Ca2+ signalling is its role in regulating cell proliferation, such as the activation of lymphocytes. The Ca2+ signal needs to be present for over two hours and this prolonged period of signalling depends upon the entry of external Ca2+ through a process of capacitative Ca2+ entry. The Ca2+ signal stimulates gene transcription and thus initiates the cell cycle processes that culminate in cell division.

Animals↗
PubMed2001

Odor-evoked calcium signals in dendrites of rat mitral cells.

Mitral cell dendrites do more than passively integrate and convey synaptic potentials to the soma, they release transmitter onto local interneurones to mediate recurrent and lateral inhibition. Several mechanisms may control the level of dendritic intracellular calcium ([Ca(2+)]) and define timing for dendritic release. Here we investigated in vivo, how odor controls calcium dynamics in mitral cell dendrites by combining intracellular recording and two-photon microscopy imaging of [Ca(2+)]. During odor stimulation, two types of [Ca(2+)] changes accompany membrane potential oscillations that are phase-locked with the respiratory cycle: (i) one is graded and parallels the membrane potential, even below the threshold for action potential firing; (ii) a second is transient, triggered by sodium action potentials that invade the entire dendritic tree. These results indicate that mitral cell dendritic compartments are synchronized by action potentials and suggest that the efficacy of dendritic synapses is finely tuned by odor-evoked graded changes in [Ca(2+)].

Action Potentials↗