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Regulation of neuronal ion channels via P2Y receptors 总被引:1,自引:0,他引:1
Within the last 15 years, at least 8 different G protein-coupled P2Y receptors have been characterized. These mediate slow metabotropic effects of nucleotides in neurons as well as non-neural cells, as opposed to the fast ionotropic effects which are mediated by P2X receptors. One class of effector systems regulated by various G protein-coupled receptors are voltage-gated and ligand-gated ion channels. This review summarizes the current knowledge about the modulation of such neuronal ion channels via P2Y receptors. The regulated proteins include voltage-gated Ca2+ and K+ channels, as well as N-methyl-d-aspartate, vanilloid, and P2X receptors, and the regulating entities include most of the known P2Y receptor subtypes. The functional consequences of the modulation of ion channels by nucleotides acting at pre- or postsynaptic P2Y receptors are changes in the strength of synaptic transmission. Accordingly, ATP and related nucleotides may act not only as fast transmitters (via P2X receptors) in the nervous system, but also as neuromodulators (via P2Y receptors). Hence, nucleotides are as universal transmitters as, for instance, acetylcholine, glutamate, or -aminobutyric acid. 相似文献
3.
Hideaki Ando Katsuhiro KawaaiKatsuhiko Mikoshiba 《Biochimica et Biophysica Acta (BBA)/Molecular Cell Research》2014
IRBIT (also called AHCYL1) was originally identified as a binding protein of the intracellular Ca2 + channel inositol 1,4,5-trisphosphate (IP3) receptor and functions as an inhibitory regulator of this receptor. Unexpectedly, many functions have subsequently been identified for IRBIT including the activation of multiple ion channels and ion transporters, such as the Na+/HCO3− co-transporter NBCe1-B, the Na+/H+ exchanger NHE3, the Cl− channel cystic fibrosis transmembrane conductance regulator (CFTR), and the Cl−/HCO3− exchanger Slc26a6. The characteristic serine-rich region in IRBIT plays a critical role in the functions of this protein. In this review, we describe the evolution, domain structure, expression pattern, and physiological roles of IRBIT and discuss the potential molecular mechanisms underlying the coordinated regulation of these diverse ion channels/transporters through IRBIT. This article is part of a Special Issue entitled: Calcium signaling in health and disease. Guest Editors: Geert Bultynck, Jacques Haiech, Claus W. Heizmann, Joachim Krebs, and Marc Moreau. 相似文献
4.
da-Silva WS Bomfim FM Galina A de Meis L 《Biochemical and biophysical research communications》2003,307(3):472-476
Maize root tonoplasts are able to accumulate Ca(2+) using the energy derived from the H(+) gradient formed during PP(i) hydrolysis. Oxalate increases 6- to 10-fold the amount of Ca(2+) accumulated by tonoplast. Two apparently different K(s) values for Ca(2+) with values of 0.36 and 4.70 microM were detected when oxalate was included in the medium and the free Ca(2+) concentration in the medium was buffered with the use of EGTA. Binding of Ca(2+) to the outer surface of tonoplasts inhibits the outflow of Ca(2+) previously accumulated by the tonoplast, half-maximal inhibition being observed in presence of 1 microM Ca(2+). Thapsigargin, a specific inhibitor of Ca(2+)-ATPase, inhibits the Ca(2+) uptake driven by H(+) gradient but does not inhibit the hydrolysis of PP(i) nor the formation of a H(+) gradient. 相似文献
5.
A family of auxiliary beta subunits coassemble with Slo alpha subunit to form Ca(2)+-regulated, voltage-activated BK-type K(+) channels. The beta subunits play an important role in regulating the functional properties of the resulting channel protein, including apparent Ca(2)+ dependence and inactivation. The beta3b auxiliary subunit, when coexpressed with the Slo alpha subunit, results in a particularly rapid ( approximately 1 ms), but incomplete inactivation, mediated by the cytosolic NH(2) terminus of the beta3b subunit (Xia et al. 2000). Here, we evaluate whether a simple block of the open channel by the NH(2)-terminal domain accounts for the inactivation mechanism. Analysis of the onset of block, recovery from block, time-dependent changes in the shape of instantaneous current-voltage curves, and properties of deactivation tails suggest that a simple, one step blocking reaction is insufficient to explain the observed currents. Rather, blockade can be largely accounted for by a two-step blocking mechanism (C(n) <---> O(n) <---> O(*)(n) <---> I(n)) in which preblocked open states (O*(n)) precede blocked states (I(n)). The transitions between O* and I are exceedingly rapid accounting for an almost instantaneous block or unblock of open channels observed with changes in potential. However, the macroscopic current relaxations are determined primarily by slower transitions between O and O*. We propose that the O to O* transition corresponds to binding of the NH(2)-terminal inactivation domain to a receptor site. Blockade of current subsequently reflects either additional movement of the NH(2)-terminal domain into a position that hinders ion permeation or a gating transition to a closed state induced by binding of the NH(2) terminus. 相似文献
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Gating properties conferred on BK channels by the beta3b auxiliary subunit in the absence of its NH(2)- and COOH termini 总被引:2,自引:0,他引:2
Both beta1 and beta2 auxiliary subunits of the BK-type K(+) channel family profoundly regulate the apparent Ca(2)+ sensitivity of BK-type Ca(2)+-activated K(+) channels. Each produces a pronounced leftward shift in the voltage of half-activation (V(0.5)) at a given Ca(2)+ concentration, particularly at Ca(2)+ above 1 microM. In contrast, the rapidly inactivating beta3b auxiliary produces a leftward shift in activation at Ca(2)+ below 1 microM. In the companion work (Lingle, C.J., X.-H. Zeng, J.-P. Ding, and X.-M. Xia. 2001. J. Gen. Physiol. 117:583-605, this issue), we have shown that some of the apparent beta3b-mediated shift in activation at low Ca(2)+ arises from rapid unblocking of inactivated channels, unlike the actions of the beta1 and beta2 subunits. Here, we compare effects of the beta3b subunit that arise from inactivation, per se, versus those that may arise from other functional effects of the subunit. In particular, we examine gating properties of the beta3b subunit and compare it to beta3b constructs lacking either the NH(2)- or COOH terminus or both. The results demonstrate that, although the NH(2) terminus appears to be the primary determinant of the beta3b-mediated shift in V(0.5) at low Ca(2)+, removal of the NH(2) terminus reveals two other interesting aspects of the action of the beta3b subunit. First, the conductance-voltage curves for activation of channels containing the beta3b subunit are best described by a double Boltzmann shape, which is proposed to arise from two independent voltage-dependent activation steps. Second, the presence of the beta3b subunit results in channels that exhibit an anomalous instantaneous outward current rectification that is correlated with a voltage dependence in the time-averaged single-channel current. The two effects appear to be unrelated, but indicative of the variety of ways that interactions between beta and alpha subunits can affect BK channel function. The COOH terminus of the beta3b subunit produces no discernible functional effects. 相似文献
8.
The effect of intracellular cAMP and cystic fibrosis conductance regulator (CFTR) protein on the calcium-activated chloride current (ICaCl) present in parotid acinar cells was studied using the patch clamp technique. Application of 1 mM of 8-(4-chlorophenylthio)adenosine 3':5'-cyclic monophosphate (CPT-cAMP), a permeable analog of cAMP, inhibited ICaCl only at positive potentials. This inhibition was partially abolished in cells dialyzed with 20 nM PKI 6-22 amide, a potent peptide that specifically inhibits PKA. Because cAMP is an activator of the CFTR Cl- channel, a known regulator of ICaCl, we also investigated if the inhibition of ICaCl was mediated by activation of CFTR. To test this idea, we added 1 mM CPT-cAMP to acinar cells isolated from knockout animals that do not express the CFTR channel. In these cells the cAMP effect was totally abolished. Thus, our data provide evidence that cAMP regulates ICaCl by a dual mechanism involving PKA and CFTR. 相似文献
9.
Kai Y. Xu Weizhong Zhu Ling Chen Christopher DeFilippi Jin Zhang Rui-Ping Xiao 《Biochemical and biophysical research communications》2011,(2):200
(Na++K+)-ATPase (NKA) mediates positive inotropy in the heart. Extensive studies have demonstrated that the reverse-mode Na+/Ca2+-exchanger (NCX) plays a critical role in increasing intracellular Ca2+ concentration through the inhibition of NKA-induced positive inotropy by cardiac glycosides. Little is known about the nature of the NCX functional mode in the activation of NKA-induced positive inotropy. Here, we examined the effect of an NKA activator SSA412 antibody on 45Ca influx in isolated rat myocytes and found that KB-R7943, a NCX reverse-mode inhibitor, fails to inhibit the activation of NKA-induced 45Ca influx, suggesting that the Ca2+ influx via the reverse-mode NCX does not mediate this process. Nifedipine, an L-type Ca2+ channel (LTCC) inhibitor, completely blocks the activation of NKA-induced 45Ca influx, suggesting that the LTCC is responsible for the moderate increase in intracellular Ca2+. In contrast, the inhibition of NKA by ouabain induces 4.7-fold 45Ca influx compared with the condition of activation of NKA. Moreover, approximately 70% of ouabain-induced 45Ca influx was obstructed by KB-R7943 and only 30% was impeded by nifedipine, indicating that both the LTCC and the NCX contribute to the rise in intracellular Ca2+ and that the NCX reverse-mode is the major source for the 45Ca influx induced by the inhibition of NKA. This study provides direct evidence to demonstrate that the activation of NKA-induced Ca2+ increase is independent of the reverse-mode NCX and pinpoints a mechanistic distinction between the activation and inhibition of the NKA-mediated Ca2+ influx path ways in cardiomyocytes. 相似文献
10.
An auxiliary beta2 subunit, when coexpressed with Slo alpha subunits, produces inactivation of the resulting large-conductance, Ca(2+) and voltage-dependent K(+) (BK-type) channels. Inactivation is mediated by the cytosolic NH(2) terminus of the beta2 subunit. To understand the structural requirements for inactivation, we have done a mutational analysis of the role of the NH(2) terminus in the inactivation process. The beta2 NH(2) terminus contains 46 residues thought to be cytosolic to the first transmembrane segment (TM1). Here, we address two issues. First, we define the key segment of residues that mediates inactivation. Second, we examine the role of the linker between the inactivation segment and TM1. The results show that the critical determinant for inactivation is an initial segment of three amino acids (residues 2-4: FIW) after the initiation methionine. Deletions that scan positions from residue 5 through residue 36 alter inactivation, but do not abolish it. In contrast, deletion of FIW or combinations of point mutations within the FIW triplet abolish inactivation. Mutational analysis of the three initial residues argues that inactivation does not result from a well-defined structure formed by this epitope. Inactivation may be better explained by linear entry of the NH(2)-terminal peptide segment into the permeation pathway with residue hydrophobicity and size influencing the onset and recovery from inactivation. Examination of the ability of artificial, polymeric linkers to support inactivation suggests that a variety of amino acid sequences can serve as adequate linkers as long as they contain a minimum of 12 residues between the first transmembrane segment and the FIW triplet. Thus, neither a specific distribution of charge on the linker nor a specific structure in the linker is required to support the inactivation process. 相似文献
11.
In the last 15 years, remarkable progress has been realized in identifying the genes that encode the ion-transporting proteins involved in exocrine gland function, including salivary glands. Among these proteins, Ca2+-dependent K+ channels take part in key functions including membrane potential regulation, fluid movement and K+ secretion in exocrine glands. Two K+ channels have been identified in exocrine salivary glands: (1) a Ca2+-activated K+ channel of intermediate single channel conductance encoded by the KCNN4 gene, and (2) a voltage- and Ca2+-dependent K+ channel of large single channel conductance encoded by the KCNMA1 gene. This review focuses on the physiological roles of Ca2+-dependent K+ channels in exocrine salivary glands. We also discuss interesting recent findings on the regulation of Ca2+-dependent K+ channels by protein–protein interactions that may significantly impact exocrine gland physiology. 相似文献
12.
Florian Lang Christos Stournaras 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2014,369(1638)
Ion transport across the cell membrane mediated by channels and carriers participate in the regulation of tumour cell survival, death and motility. Moreover, the altered regulation of channels and carriers is part of neoplastic transformation. Experimental modification of channel and transporter activity impacts tumour cell survival, proliferation, malignant progression, invasive behaviour or therapy resistance of tumour cells. A wide variety of distinct Ca2+ permeable channels, K+ channels, Na+ channels and anion channels have been implicated in tumour growth and metastasis. Further experimental information is, however, needed to define the specific role of individual channel isoforms critically important for malignancy. Compelling experimental evidence supports the assumption that the pharmacological inhibition of ion channels or their regulators may be attractive targets to counteract tumour growth, prevent metastasis and overcome therapy resistance of tumour cells. This short review discusses the role of Ca2+ permeable channels, K+ channels, Na+ channels and anion channels in tumour growth and metastasis and the therapeutic potential of respective inhibitors. 相似文献
13.
Store-operated Ca2+ entry (SOCE) is a widespread mechanism to elevate the intracellular Ca2+ concentrations and stimulate downstream signaling pathways affecting proliferation, secretion, differentiation and death in different cell types. In immune cells, immune receptor stimulation induces intracellular Ca2+ store depletion that subsequently activates Ca2+-release-activated-Ca2+ (CRAC) channels, a prototype of store-operated Ca2+ (SOC) channels. CRAC channel opening leads to activation of diverse downstream signaling pathways affecting proliferation, differentiation, cytokine production and cell death. Recent identification of STIM1 as the endoplasmic reticulum Ca2+ sensor and Orai1 as the pore subunit of CRAC channels has provided the much-needed molecular tools to dissect the mechanism of activation and regulation of CRAC channels. In this review, we discuss the recent advances in understanding the associating partners and posttranslational modifications of Orai1 and STIM1 proteins that regulate diverse aspects of CRAC channel function. 相似文献
14.
《Channels (Austin, Tex.)》2013,7(3):193-202
Prolactin (PRL) activates PRL receptor isoforms to exert regulation of specific neuronal circuitries, and to control numerous physiological and clinically-relevant functions including; maternal behavior, energy balance and food intake, stress and trauma responses, anxiety, neurogenesis, migraine and pain. PRL controls these critical functions by regulating receptor potential thresholds, neuronal excitability and/or neurotransmission efficiency. PRL also influences neuronal functions via activation of certain neurons, resulting in Ca2+ influx and/or electrical firing with subsequent release of neurotransmitters. Although PRL was identified almost a century ago, very little specific information is known about how PRL regulates neuronal functions. Nevertheless, important initial steps have recently been made including the identification of PRL-induced transient signaling pathways in neurons and the modulation of neuronal transient receptor potential (TRP) and Ca2+-dependent K+ channels by PRL. In this review, we summarize current knowledge and recent progress in understanding the regulation of neuronal excitability and channels by PRL. 相似文献
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Prolactin (PRL) activates PRL receptor isoforms to exert regulation of specific neuronal circuitries, and to control numerous physiological and clinically-relevant functions including; maternal behavior, energy balance and food intake, stress and trauma responses, anxiety, neurogenesis, migraine and pain. PRL controls these critical functions by regulating receptor potential thresholds, neuronal excitability and/or neurotransmission efficiency. PRL also influences neuronal functions via activation of certain neurons, resulting in Ca2+ influx and/or electrical firing with subsequent release of neurotransmitters. Although PRL was identified almost a century ago, very little specific information is known about how PRL regulates neuronal functions. Nevertheless, important initial steps have recently been made including the identification of PRL-induced transient signaling pathways in neurons and the modulation of neuronal transient receptor potential (TRP) and Ca2+-dependent K+ channels by PRL. In this review, we summarize current knowledge and recent progress in understanding the regulation of neuronal excitability and channels by PRL. 相似文献
17.
M. A. Gray J. R. Greenwell A. J. Garton B. E. Argent 《The Journal of membrane biology》1990,115(3):203-215
Summary Using the patch-clamp technique we have identified a Ca2+-sensitive, voltage-dependent, maxi-K+ channel on the basolateral surface of rat pancreatic duct cells. The channel had a conductance of 200 pS in excised patches bathed in symmetrical 150mm K+, and was blocked by 1mm Ba2+. Channel openstate probability (P
o
) on unstimulated cells was very low, but was markedly increased by exposing the cells to secretin, dibutyryl cyclic AMP, forskolin or isobutylmethylxanthine. Stimulation also shifted theP
o
/voltage relationship towards hyperpolarizing potentials, but channel conductance was unchanged. If patches were excised from stimulated cells into the inside-out configuration,P
o
remained high, and was not markedly reduced by lowering bath (cytoplasmic) Ca2+ concentration from 2mm to 0.1 m. However, activated channels were still blocked by 1mm Ba2+. ChannelP
o
was also increased by exposing the cytoplasmic face of excised patches to the purified catalytic subunit of cyclic AMP-dependent protein kinase., We conclude that cyclic AMP-dependent phosphorylation can activate maxi-K+ channels on pancreatic duct cells via a stable modification of the channel protein itself, or a closely associated regulatory subunit, and that phosphorylation alters the responsiveness of the channels to Ca2+. Physiologically, these K+ channels may contribute to the basolateral K+ conductance of the duct cell and, by providing a pathway for current flow across the basolateral membrane, play an important role in pancreatic bicarbonate secretion. 相似文献
18.
Srivastava S Cala SE Coetzee WA Artman M 《Biochemical and biophysical research communications》2007,355(2):338-341
Phospholemman (PLM) is a small sarcolemmal protein that modulates the activities of Na(+)/K(+)-ATPase and the Na(+)/Ca(2+) exchanger (NCX), thus contributing to the maintenance of intracellular Na(+) and Ca(2+) homeostasis. We characterized the expression and subcellular localization of PLM, NCX, and the Na(+)/K(+)-ATPase alpha1-subunit during perinatal development. Western blotting demonstrates that PLM (15kDa), NCX (120kDa), and Na(+)/K(+)-ATPase alpha-1 (approximately 100kDa) proteins are all more than 2-fold higher in ventricular membrane fractions from newborn rabbit hearts (1-4-day old) compared to adult hearts. Our immunocytochemistry data demonstrate that PLM, NCX, and Na(+)/K(+)-ATPase are all expressed at the sarcolemma of newborn ventricular myocytes. Taken together, our data indicate that PLM, NCX, and Na(+)/K(+)-ATPase alpha-1 proteins have similar developmental expression patterns in rabbit ventricular myocardium. Thus, PLM may have an important regulatory role in maintaining cardiac Na(+) and Ca(2+) homeostasis during perinatal maturation. 相似文献
19.
ATP-sensitive inward rectifier and voltage- and calcium-activated K+ channels in cultured pancreatic islet cells 总被引:15,自引:0,他引:15
Summary K+ channels in cultured rat pancreatic islet cells have been studied using patch-clamp single-channel recording techniques in cell-attached and excised inside-out and outside-out membrane patches. Three different K+-selective channels have been found. Two inward rectifier K+ channels with slope conductances of about 4 and 17 pS recorded under quasi-physiological cation gradients (Na+ outside, K+ inside) and maximal conductances recorded in symmetrical K+-rich solutions of about 30 and 75 pS, respectively. A voltage- and calcium-activated K– channel was recorded with a slope conductance of about 90 pS under the same conditions and a maximal conductance recorded in symmetrical K+-rich solutions of about 250 pS. Single-channel current recording in the cell-attached conformation revealed a continuous low level of activity in an apparently small number of both the inward rectifier K+ channels. But when membrane patches were excised from the intact cell a much larger number of inward rectifier K+ channels became transiently activated before showing an irreversible decline. In excised patches opening and closing of both the inward rectifier K+ channels were unaffected by voltage, internal Ca2+ or externally applied tetraethyl-ammonium (TEA) but the probability of opening of both inward rectifier K+ channels was reduced by internally applied 1–5mm adenosine-5-triphosphate (ATP). The large K+ channel was not operational in cell-attached membrane patches, but in excised patches it could be activated at negative membrane potentials by 10–7 to 10–6
m internal Ca2+ and blocked by 5–10mm external TEA. 相似文献
20.
S. N. Orlov G. A. Skryabin 《Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology》1993,163(5):413-420
In carp erythrocytes, noradrenaline (10-6 mol·l-1) induces a 30- to 40-fold activation of Na+/H+ exchange (the ethylisopropylamiloride-inhibited component of the 22Na influx) and a fourfold stimulation of the Na+, K+ pump (ouabain-inhibited component of 86Rb influx). In both cases the effect of noradrenaline is blocked by propranolol but not phentolamine and is imitated by forskolin. An activator of protein kinase C (-phorbol 12-myristate, 13-acetate) increases Na+/H+ exchange by 10 times and decreases the Na+, K+ pump activity by 20–30 percent. In the presence of ethylisopropylamiloride the increment of the Na+, K+ pump activity induced by noradrenaline is reduced by 35–45 percent, indicating the existence of a Na+/H+ exchange-independent mechanism of the Na+, K+ pump regulation by -adrenergic catecholamines. Hypertonic shrinkage of carp erythrocytes results in a 40- to 80-fold activation of Na+/H+ exchange, whereas hypotonic swelling induces an increase in the rate of 86Rb+ efflux which is inhibited by furosemide by about 30–40 percent. The rate of pH0 recovery in response to acidification or alkalinization in rat erythrocytes is approximately 15 times as fast as in carp erythrocytes. Unlike in rat erythrocytes, valinomycin does not cause an alkalinization of incubation medium in carp erythrocytes indicating the absence of conductive pathway in the operation of anion transporter protein. A scheme is suggested which describes the interrelation of Na+/H+ exchange, Na+, K+ pump and a non-identified system providing for K+ efflux in cell swelling, regulation of cell volume and cytoplasmic pH in fish erythrocytes under conditions of deep hypoxia and high activity.Abbreviations cAMP
cyclic adenosine monophosphate
- CCCP
carbonylcyamide m-chlorophenylhydrazone
- DMSO
dimethylsulphoxide
- EIPA
ethylisopropylamiloride
- NA
noradrenaline
- PMA
-phorbol 12-myristate, 13-acetate
- RVD
regulatory volume decrease
- RVI
regulatory volume increase 相似文献