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PubMed1996

Effects of cerebral ischemia on N-methyl-D-aspartate and dihydropyridine-sensitive calcium currents. An electrophysiological study in the rat hippocampus in situ.

BACKGROUND AND PURPOSE: During cerebral ischemia, both promoting and limiting factors are present for activation of the N-methyl-D-aspartate (NMDA) receptor ion channel and the dihydropyridine (DHP)-sensitive Ca2+ channels. We investigated the activity of these channels during ischemia and reperfusion in the rat hippocampus in situ. METHODS: Reversible ischemia was induced by bilateral carotid artery ligation. NMDA and BAY K8644 were applied by iontophoresis or pneumatic ejection, and extracellular field potential and resistance changes were recorded from the CA1 region of the rat hippocampus. Resting membrane potentials of the CA1 neurons were also recorded. RESULTS: DC potential shifts produced by NMDA and BAY K8644 were reduced when ischemia depressed the evoked activity more than 50%. They disappeared on total failure of synaptic transmission and recovered during reperfusion. When the evoked activity was depressed less than 50%, DC shifts were greater than their preischemic values; however, BAY K8644-induced potentiation did not reach statistical significance. CA1 neurons were depolarized during ischemia. CONCLUSIONS: These data suggest that ischemia severe enough to cause transmission failure inactivates NMDA and DHP-sensitive Ca2+ currents. During less intense ischemia and reperfusion, NMDA and DHP-sensitive Ca2+ channels are functional, and their overactivation may lead to neurotoxicity.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2002

Regulation of nuclear pore complex conformation by IP(3) receptor activation.

In recent years, both the molecular architecture and functional dynamics of nuclear pore complexes (NPCs) have been revealed with increasing detail. These large, supramolecular assemblages of proteins form channels that span the nuclear envelope of cells, acting as crucial regulators of nuclear import and export. From the cytoplasmic face of the nuclear envelope, nuclear pore complexes exhibit an eightfold symmetric ring structure encompassing a central lumen. The lumen often appears occupied by an additional structure alternatively referred to as the central granule, nuclear transport complex, or nuclear plug. Previous studies have suggested that the central granule may play a role in mediating calcium-dependent regulation of diffusion across the nuclear envelope for intermediate sized molecules (10-40 kDa). Using atomic force microscopy to measure the surface topography of chemically fixed Xenopus laevis oocyte nuclear envelopes, we present measurements of the relative position of the central granule within the NPC lumen under a variety of conditions known to modify nuclear Ca(2+) stores. These measurements reveal a large, approximately 9-nm displacement of the central granule toward the cytoplasmic face of the nuclear envelope under calcium depleting conditions. Additionally, activation of nuclear inositol triphosphate (IP(3)) receptors by the specific agonist, adenophostin A, results in a concentration-dependent displacement of central granule position with an EC(50) of ~1.2 nM. The displacement of the central granule within the NPC is observed on both the cytoplasmic and nucleoplasmic faces of the nuclear envelope. The displacement is blocked upon treatment with xestospongin C, a specific inhibitor of IP(3) receptor activation. These results extend previous models of NPC conformational dynamics linking central granule position to depletion of IP(3) sensitive nuclear envelope calcium stores.

Adenosine↗
PubMed2000

I(ARC), a novel arachidonate-regulated, noncapacitative Ca(2+) entry channel.

Along with the inositol trisphosphate-induced release of stored Ca(2+), a receptor-enhanced entry of Ca(2+) is a critical component of intracellular Ca(2+) signals generated by agonists acting at receptors coupled to the activation of phospholipase C. Although the simple emptying of the intracellular Ca(2+) stores is known to be capable of activating Ca(2+) entry via the so-called "capacitative" mechanism, recent evidence suggests that Ca(2+) entry at physiological agonist concentrations, where oscillatory Ca(2+) signals are typically observed, does not conform to such a model. Instead, a noncapacitative Ca(2+) entry pathway regulated by arachidonic acid appears to be responsible for Ca(2+) entry under these conditions. Using whole-cell patch clamp techniques we demonstrate that low concentrations of arachidonic acid activate a Ca(2+)-selective current that is superficially similar to the store-operated current I(CRAC), but which also demonstrates certain distinct features. We have named this novel current I(ARC) (for arachidonate-regulated calcium current). Importantly, I(ARC) can be readily activated in cells whose Ca(2+) stores have been maximally depleted. I(ARC) represents a novel Ca(2+) entry pathway that is entirely separate from those activated by store depletion and is specifically activated at physiological levels of stimulation.

Arachidonic Acid↗
PubMed2004

P2Y2-receptor-mediated activation of a contralateral, lanthanide-sensitive calcium entry pathway in the human airway epithelium.

1. Receptor-mediated calcium entry (RMCE) was examined in well-differentiated cultures of normal human bronchial epithelial cells (HBECs). Changes in intracellular free Ca(2+) ([Ca(2+)](i)) were quantified using fluorescence ratio imaging of Fura-2-loaded cells during perfusion with Ca(2+) mobilizing agonists. 2. Initial studies revealed an agonist potency of ATP=uridine triphosphate (UTP) >ADP=uridine diphosphate, consistent with purinergic activation of an apical P2Y(2)-receptor mediating the increase in [Ca(2+)](i) in HBECs. 3. Apical UTP (30 microm) induced a sustained period of elevated [Ca(2+)](i) between 300 and 600 s following agonist stimulation that extracellular Ca(2+) free studies indicated was dominated by Ca(2+) influx. 4. RMCE was inhibited by 100 nm La(3+) (83+/-3%) or Gd(3+) (95+/-7%) (P<0.005, n=4-11) and was partially attenuated by Ni(2+) (1 mm) (58.7+/-5.0%, P<0.005, n=9). 5. RMCE was also partially sensitive (< 25% inhibition, P<0.01) to the cation channel blockers SKF96365 (30 microm) and econazole (30 microm), but was insensitive to both verapamil (1 microm) and ruthenium red (10 microm). 6. Using either a sided Ca(2+) readdition protocol or unilateral La(3+), established that the RMCE pathway was located exclusively on the basolateral membrane. 7. The pharmacological sensitivity of the P2Y(2)-receptor activated Ca(2+) entry pathway in the human airway epithelium is inconsistent with the established profile of TRP channel families and is therefore likely to be of an as-yet uncharacterized molecular identity.

Area Under Curve↗
PubMed1996

Antidystonic effects of L-type Ca2+ channel antagonists in a hamster model of idiopathic dystonia.

The effects of selective L-type Ca2+ channel antagonists on severity of dystonia were investigated in a mutant hamster model of idiopathic generalized dystonia. Nimodipine and diltiazem significantly decreased the severity of dystonia. Nimodipine was more potent in this respect and did not cause any behavioral side effects. The present data therefore suggest that Ca2+ channel antagonists could be useful in the treatment of idiopathic dystonia. The antidystonic effect of diltiazem and nimodipine may be based on their antidopaminergic action. However, the lack of significant effects of the L-type channel agonist (+/-)-BAY k-8644 (1-5 mg/kg; methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoro-methylphenyl) -pyridine-5-carboxylate)) on severity of dystonia may indicate that voltage-gated Ca2+ channels are not critically involved in the pathophysiology of dystonia in mutant hamsters.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2002

Biphasic effects of oxethazaine, a topical anesthetic, on the intracellular Ca(2+) concentration of PC12 cells.

There have been few reports on the mechanism(s) of action of oxethazaine (OXZ) despite its potent local anesthetic action. Generally, local anesthetics (LAs) not only inhibit Na(+) channels but also affect various membrane functions. In the present study, using PC12 cells as a nerve cell model, the effects of OXZ on intracellular Ca(2+) concentration ([Ca(2+)](i)) were examined in relation to cytotoxicity and dopamine release. [Ca(2+)](i) was determined by the quin2 method. In resting cells, (6-10)x10(-5)M OXZ produced lactate dehydrogenase leakage, which was Ca(2+)-dependent, inhibited by metal Ca(2+) channel blockers, and preceded by a marked increase in [Ca(2+)](i). Some other LAs showed no cytotoxicity at these concentrations. In K(+)-depolarized cells, however, lower concentrations of OXZ (10(-6)-10(-7)M), that had no effect on resting [Ca(2+)](i), inhibited both the dopamine release and the increase of [Ca(2+)](i) in parallel. The inhibitory potency against the [Ca(2+)](i) increase was in the order of nifedipine>OXZ approximately verapamil>diltiazem, and OXZ acted additively on the Ca(2+) channel blockers. OXZ showed the least effect on K(+)-depolarization as determined by bisoxonol uptake. OXZ also inhibited the increase in [Ca(2+)](i) induced by S(-)-BAY K 8644, a Ca(2+) channel agonist. These observations suggested that low concentrations of OXZ interact with L-type Ca(2+) channels. The biphasic effects of OXZ on Ca(2+) movement may be due to a unique chemical structure, and may participate in and complicate the understanding of the potent pharmacological and toxicological actions of OXZ.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2005

Lamotrigine has an anxiolytic-like profile in the rat conditioned emotional response test of anxiety: a potential role for sodium channels?

RATIONALE: Many anticonvulsants are used in disorders other than epilepsy. For example, lamotrigine is reported to be effective in post-traumatic stress disorder and mania. OBJECTIVE: We assessed the effects of the anticonvulsants lamotrigine, valproate and carbamazepine in an animal model of anxiety. We assessed a wide range of pharmacological tools to delineate the mechanism of lamotrigine's anxiolytic effect. METHODS: We assessed these compounds in the rat conditioned emotional response (CER) test of anxiety. RESULTS: Lamotrigine (30-80 mg/kg) dose-dependently and reproducibly engendered an anxiolytic response in this test, with similar efficacy to benzodiazepines. Carbamazepine (20-40 mg/kg) and riluzole (10 mg/kg), which block Na+ channels by a similar mechanism as lamotrigine, were also anxiolytic. By contrast, valproate (100-600 mg/kg) was inactive and appears to differ in its interaction with Na+ channels. The SSRI paroxetine, the GABA(A) receptor positive modulator propofol, the NMDA antagonists memantine and (+)MK-801, and the Ca2+ channel antagonist nifedipine were all inactive in the CER test, suggesting these mechanisms may not mediate the anxiolytic effect of lamotrigine. More directly, we showed that the anxiolytic effect of lamotrigine could be blocked by co-administering rats with the Na+ channel activator veratrine (0.1 mg/kg). By contrast, neither the Ca2+ channel agonist BAYK8644 (0.5 mg/kg) nor the 5-HT1A or 5-HT(1/2) antagonists WAY100635 (0.3 mg/kg) and metergoline (3 mg/kg), respectively, were able to block the effect. CONCLUSION: Lamotrigine's anxiolytic effect in the CER test may be mediated via block of Na+ channels, and this may represent a target for the development of novel anxiolytics.

Animals↗
PubMed1998

Mu-opioid and GABA(B) receptors modulate different types of Ca2+ currents in rat nodose ganglion neurons.

Whole-cell patch-clamp recordings were obtained from nodose ganglion neurons acutely dissociated from 10-30-day-old rats to characterize the Ca2+ channel types that are modulated by GABA(B) and mu-opioid receptors. Five components of high-threshold current were distinguished on the basis of their sensitivity to blockade by omega-conotoxin GVIA, nifedipine, omega-agatoxin IVA and omega-conotoxin MVIIC. Administration of the mu-opioid agonist H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol (0.3-1 mM) or the GABA(B) agonist baclofen in saturating concentrations suppressed high-threshold Ca2+ currents by 49.9+/-2.4% (n=69) and 18.7+/-2.1% (n=35), respectively. The inhibition by H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol exceeded that by baclofen in virtually all neurons that responded to both agonists (67%), and occlusion experiments revealed that responses to mu-opioid and GABA(B) receptor activation were not linearly additive. In addition, administration of staurosporine, a non-selective inhibitor of protein kinase A and C, did not affect the inhibitory responses to either agonist or prevent the occlusion of baclofen-induced current inhibition by H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol. Blockade of N-type channels by omega-conotoxin GVIA eliminated current suppression by baclofen in all cells tested (n=11). Mu-opioid-induced inhibition in current was abolished by omega-conotoxin GVIA in 12 of 30 neurons tested, but was only partially reduced in the remaining 18 neurons. In the latter cells administration of omega-agatoxin IVA reduced, but did not eliminate the mu-opioid sensitive current component that persisted after blockade of N-type channels. This residual component of mu-opioid-sensitive current was blocked completely by omega-conotoxin MVIIC in nine neurons, whereas responses to H-Tyr-D-Ala-Gly-Phe(N-Me)-Gly-ol were still recorded in the remaining cells after administration of these Ca2+ channel toxins and nifedipine. Dihydropyridine-sensitive (L-type) current was not affected by activation of mu-opioid or GABA(B) receptors in any of the neurons. These data indicate that in nodose ganglion neurons mu-opioid receptors are negatively coupled to N-, P- and Q-type channels as well as to a fourth, unidentified toxin-resistant Ca2+ channel. In contrast, GABA(B) receptors are coupled only to N-type channels. Furthermore, the results do not support a role for either protein kinase C or A in the modulatory pathway(s) coupling mu-opioid and GABA(B) receptors to Ca2+ channels, but rather lend credence to the notion that the signalling mechanisms utilized by these two receptors might simply compete for inhibitory control of a common pool of N-type channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Cholesterol inhibits spontaneous action potentials and calcium currents in guinea pig gallbladder smooth muscle.

Elevated cholesterol decreases agonist-induced contractility and enhances stone formation in the gallbladder. The current study was conducted to determine if and how the electrical properties and ionic conductances of gallbladder smooth muscle are altered by elevated cholesterol. Cholesterol was delivered as a complex with cyclodextrin, and effects were evaluated with intracellular recordings from intact gallbladder and whole cell patch-clamp recordings from isolated cells. Cholesterol significantly attenuated the spontaneous action potentials of intact tissue. Furthermore, calcium-dependent action potentials and calcium currents were reduced in the intact tissue and in isolated cells, respectively. However, neither membrane potential hyperpolarizations induced by the ATP-sensitive potassium channel opener, pinacidil, nor voltage-activated outward potassium currents were affected by cholesterol. Hyperpolarizations elicited by calcitonin gene-related peptide were reduced by cholesterol enrichment, indicating potential changes in receptor ligand binding and/or second messenger interactions. These data indicate that excess cholesterol can contribute to gallbladder stasis by affecting calcium channel activity, whereas potassium channels remained unaffected. In addition, cholesterol enrichment may also modulate receptor ligand behavior and/or second messenger interactions.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2001

Perchlorate stimulates insulin secretion by shifting the gating of L-type Ca2+ currents in mouse pancreatic B-cells towards negative potentials.

The effects of the chaotrophic anion perchlorate (ClO4-) on glucose-induced electrical activity, exocytosis and ion channel activity in mouse pancreatic B-cells were investigated by patch-clamp recordings and capacitance measurements. ClO4- stimulated glucose-induced electrical activity and increased the action potential frequency by 70% whilst not affecting the membrane potential when applied in the presence of a subthreshold concentration of the sugar. ClO4- did not influence ATP-dependent K (KATP) channel activity and voltage-gated delayed K+ current. Similarly, ClO4- had no effect on Ca2+-dependent exocytosis. The stimulation of electrical activity and insulin secretion was instead attributable to an enhancement of the whole-cell Ca2+ current. This effect was particularly pronounced at voltages around the threshold for action potential initiation and a doubling of the current amplitude was observed at -30 mV. This was due to a 7-mV shift in the gating of the Ca2+ current towards negative voltages. The action of ClO4- was more pronounced when added in the presence of 0.1 mM BAY K8644, whereas no stimulation was observed when applied at a maximal concentration of the agonist (1 mM). Single-channel recordings revealed that the effect of ClO4- on whole-cell currents was principally due to a 60% increase in the mean duration of the long openings and the number of active channels. We propose that ClO4- stimulates insulin secretion and electrical activity by exerting a BAY K8644-like action on Ca2+ channel gating.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Ionic currents underlying HTRP3 mediated agonist-dependent Ca2+ influx in stably transfected HEK293 cells.

hTrp3 is a human homologue of the Drosophila gene responsible for a transient receptor potential (trp) mutation. When stably expressed in HEK293 cells, hTrp3 formed ion channels that were active under resting conditions but could be further stimulated by carbachol or ATP via endogenous muscarinic or purinergic receptors, respectively. Agonist evoked currents reversed polarity near 0 mV in physiological ionic conditions and were associated with a significant increase in the current variance. These results suggest the involvement of a non-selective cation channel with relatively large unitary amplitude. Consistent with this, resolved unitary events had a conductance of approximately 60 pS in the negative voltage range and an extrapolated reversal potential near 0 mV.

Adenosine Triphosphate↗
PubMed2004

Influence of intracellular Ca2+ release modulating drugs on bupivacaine infiltration anesthesia in mice.

The endoplasmic reticulum inside neurons can provide enormous amounts of releasable Ca2+ to increase cytosolic Ca2+ levels through the activation of endoplasmic membrane ion channels. Ryanodine (RyR) channels release Ca2+ into the cytosol when activated by Ca2+ influx through voltage-gated channels, or by cyclicADP ribose. Inositol tris-phosphate (IP3) channels are stimulated by phospolipid metabolism and the release of IP3. The hypothesis was tested that drugs that bind RyR or IP3 channels would affect the anesthetic potency of bupivacaine. The radiant heat tail-flick test was used to assess for anesthesia following subcutaneous infiltration of bupivacaine and Ca2+ modulating drugs in the tails of mice. No musculature is contained in the tail that could result in motor block. The RyR channel agonists 4-chloro-m-cresol and poly-L-lysine significantly reduced the anesthetic potency of bupivacaine. The plant alkaloid ryanodine elicited a bi-phasic effect, with low concentrations blocking bupivacaine anesthesia, and a high concentration enhancing anesthesia. Alternatively, the RyR channel antagonist dantrolene sodium dose-dependently increased bupivacaine's potency. However, the IP3 channel drugs were inactive. The IP3 agonist adenophostin A failed to affect bupivacaine anesthesia. Furthermore, bupivacaine was unaffected by the IP3 channel antagonists xestospongin C or low molecular weight heparin. Our results indicate that only the RyR channel drugs modulated the anesthetic effects of bupivacaine. Electrophysiological and molecular studies of sensory dorsal root ganglia neurons, the source of Adelta and C-fiber nociceptors, have demonstrated the presence of RyR3 Ca2+ release channels. This provides the first evidence that RyR channels might affect bupivacaine anesthesia in some fashion.

Anesthesia, Local↗
PubMed1989

Calcium currents in bullfrog sympathetic neurons. I. Activation kinetics and pharmacology.

The calcium current of bullfrog sympathetic neurons activates and deactivates rapidly (tau less than 3 ms). For brief depolarizations, the current can be fit reasonably well by a Hodgkin-Huxley-type model with a single gating particle of charge +3. With 2 mM Ca2+ as the charge carrier, half-maximal activation occurs at approximately -5 mV, near the voltage where activation and deactivation are slowest. When extracellular divalent ion concentrations are reduced, monovalent ions (e.g., Na+ and methylammonium) produce kinetically similar inward currents. Current carried by Ba2+ is blocked by Cd2+ at micromolar concentrations, and by 100 nM omega-conotoxin. Commercially available saxitoxin blocks the current, but different batches have quantitatively different potency. The dihydropyridine agonist Bay K 8644 induces a slight shift in activation kinetics to more negative voltages, with little effect on the peak current. Nifedipine at least partially reverses the effect of Bay K 8644, but has little effect on its own. Muscarinic agonists and other ligands that inhibit the M-type potassium current of frog sympathetic neurons have weak inhibitory effects on the calcium current as well. One interpretation of these results is that the N-type calcium current predominates in these cells, with a minor contribution of L-type current.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Acetylcholine triggers L-glutamate exocytosis via nicotinic receptors and inhibits melatonin synthesis in rat pinealocytes.

Rat pinealocytes, melatonin-secreting endocrine cells, contain peripheral glutaminergic systems. L-Glutamate is a negative regulator of melatonin synthesis through a metabotropic receptor-mediated inhibitory cAMP cascade. Previously, we reported that depolarization of pinealocytes by externally added KCl and activation of L-type Ca2+ channels resulted in secretion of L-glutamate by microvesicle exocytosis. What is unknown is how and what kinds of stimuli trigger glutamate exocytosis under physiological conditions. Here, we report that the nicotinic acetylcholine receptor can trigger glutamate exocytosis from cultured rat pinealocytes. Moreover, acetylcholine or nicotine inhibited norepinephrine-dependent serotonin N-acetyltransferase activity, which results in decreased melatonin synthesis. These activities were blocked by (2S,3S, 4S)-2-methyl-2-(carboxycyclopropyl)glycine, an antagonist of the metabotropic glutamate receptor. These results suggest that cholinergic stimulation initiates the glutaminergic signaling cascade in pineal glands and that parasympathetic neurons innervating the gland exert negative control over melatonin synthesis by way of the glutaminergic systems.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2006

Reduced cardiac L-type Ca2+ current in Ca(V)beta2-/- embryos impairs cardiac development and contraction with secondary defects in vascular maturation.

Cardiac myocyte contraction depends on transmembrane L-type Ca2+ currents and the ensuing release of Ca2+ from the sarcoplasmic reticulum. Here we show that these L-type Ca2+ currents are essential for cardiac pump function in the mouse at developmental stages where the functional significance of the heart becomes imperative to blood flow and to the continuing growth and survival of the embryo. Disruption of the Ca(V)beta2 gene, which encodes for the predominant ancillary beta subunit of cardiac Ca2+ channels, resulted in diminished L-type Ca2+ currents in cardiomyocytes of embryonic day 9.5 (E9.5). This led to a functionally compromised heart, causing defective remodeling of intra- and extraembryonic blood vessels and embryonic death following E10.5. The defects in vascular remodeling were also observed when the Ca(V)beta2 gene was selectively targeted in cardiomyocytes, demonstrating that they are secondary to cardiac failure rather than a result of the lack of Ca(V)beta2 proteins in the vasculature. Partial rescue of the Ca2+ channel currents by a Ca2+ channel agonist significantly postponed embryonic death in Ca(V)beta2-/- mice. Taken together, these data strongly support the essential role of L-type Ca2+ channel activity in cardiomyocytes for normal heart development and function and that this is a prerequisite for proper maturation of the vasculature.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Synthesis and voltage-clamp studies of methyl 1,4-dihydro-2, 6-dimethyl-5-nitro-4-(benzofurazanyl)pyridine-3-carboxylate racemates and enantiomers and of their benzofuroxanyl analogues.

Racemic methyl 1,4-dihydro-2, 6-dimethyl-5-nitro-4-(benzofurazanyl)pyridine-3-carboxylates (+/-)-10 and (+/-)-11 and their benzofuroxanyl analogues (+/-)-12 and (+/-)-13 were prepared using a modified Hantzsch reaction that involved the condensation of nitroacetone with methyl 3-aminocrotonate and the appropriate aldehydes. The racemic mixtures were resolved into the corresponding enantiomers. Whole-cell voltage-clamp studies on L-type Ca2+ channels expressed in a rat insulinoma cell line (RINm5F) showed that all the dextrorotatory antipodes were effective agonists of L-type Ca2+ currents, while the levorotatory ones were weak Ca2+ entry blockers. The (+)-enantiomer of benzofurazan-5'-yl derivative 11 demonstrated unusual activity in that, in addition to producing a potentiation of L-type currents, it interfered with the voltage-dependent gating of L-type channels by producing a net delay of their activation at low voltages. This compound represents an interesting tool to probe L-type Ca2+ channel structure and function.

Animals↗
PubMed1994

Overexpression of inositol 1,4,5-trisphosphate 3-kinase in Xenopus oocytes inhibits agonist-evoked capacitative calcium entry.

Ins(1,4,5)P3 3-kinase is a key enzyme in the regulation of Ins(1,4,5)P3. Overexpression of Ins(1,4,5)P3 3-kinase inhibited agonist-evoked and Ins(1,3,4,5)P4-evoked Ca2+ entry in Xenopus oocytes, but did not inhibit Ca2+ entry evoked by thapsigargin or non-metabolizable Ins(1,4,5)P3 analogues. The data suggest that Ins(1,4,5)P3 alone plays the crucial role in the activation of capacitative Ca2+ entry by emptying intracellular stores.

Animals↗
PubMed2000

Dihydropyridine-induced Ca2+ release from ryanodine-sensitive Ca2+ pools in human skeletal muscle cells.

Dihydropyridines (DHPs) are widely used antihypertensive drugs and inhibit excitation-contraction (E-C) coupling in vascular smooth muscle and in myocardial cells by antagonizing L-type Ca2+ channels (DHP receptors). However, contradictory reports exist about the interaction of the DHP with the skeletal muscle isoform of the DHP receptor and E-C coupling in skeletal muscle cells. Using the intracellular fluorescent Ca2+ indicator fura-2, an increase in [Ca2+]i was observed after extracellular application of nifedipine to cultured human skeletal muscle cells. The rise in [Ca2+]i was dose dependent with a calculated EC50 of 614 +/- 96 nM nifedipine and a maximum increment in [Ca2+]i of 80 +/- 3.2 nM. Similar values were obtained with nitrendipine. This effect of DHPs was restricted to differentiated skeletal muscle cells and was not seen in non-differentiated cells or in PC12 cells. In spite of the observed increase in [Ca2+]i, whole-cell patch clamp experiments revealed that 10 microM nifedipine abolished inward Ba2+ currents through L-type Ca2+ channels completely. Similar to nifedipine, (+/-)Bay K 8644, an agonist of the L-type Ca2+ channel, also increased [Ca2+]i. This effect could not be enhanced by further addition of nifedipine, suggesting that both DHPs act via a common signalling pathway. Based on the specific mechanism of the skeletal muscle E-C coupling, we propose the stabilization of a conformational state of the DHP receptor by DHPs, which is sufficient to activate the ryanodine receptor.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗