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Results for “Calcium Channels, Q-Type”

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PubMed1994

Calcium channel antagonist peptides define several components of transmitter release in the hippocampus.

The use of subtype-selective voltage-sensitive calcium channel (VSCC) antagonists has established that neurotransmitter release in mammalian brain is mediated by N-like and P-like VSCCs, and that other subtypes also contribute significantly. To determine the roles presynaptic VSCCs play in nervous system function and to evaluate the therapeutic potential of their selective inhibition, it is necessary to define further the contributions of VSCC subtypes to neurotransmitter release. The novel conopeptide, SNX-230 (omega-conopeptide MVIIC), has revealed a new VSCC subtype, the Q-type, in cerebellar granule cells. We have compared the effects of SNX-230 on release of tritiated D-aspartate ([3H]D-Asp; a non-metabolizable analog of glutamate), gamma-aminobutyric acid ([3H]GABA), and norepinephrine ([3H]NE) from rat hippocampal slices to those of the N-type VSCC blocker, SNX-111 (omega-conopeptide MVIIA), and the P-type blocker, omega-agatoxin-IVA (AgaIVA). SNX-230 blocks both [3H]D-Asp and [3H]GABA release completely, whereas AgaIVA blocks them potently but partially and SNX-111 has no effect. These results suggest that glutamate and GABA release are mediated by two VSCC subtypes, a P-type and another, perhaps Q-like. SNX-111 blocks [3H]NE release potently but partially, while SNX-230 blockade is complete, consisting of one very potent phase and one less potent phase. AgaIVA also blocks [3H]NE release potently but partially. These results suggest that at least two VSCC subtypes, an N-type and a novel non-N-type, mediate NE release. Pair-wise combinations of the three ligands indicate that at least three pharmacologically distinct components comprise [3H]NE release in the hippocampus.

Amino Acid Sequence↗

PubMedDate not supplied

Regulation of intracellular [Ca2+] and GABA release by presynaptic GABAB receptors in rat cerebrocortical synaptosomes.

In this study we determined the changes in the intracellular free Ca2+ concentration, associated with the inhibitory modulation of the exocytotic release of GABA by GABAB receptor activation in rat cerebrocortical synaptosomes. We observed that SK&F 97541 and (-)baclofen both act as agonists of the presynaptic GABAB receptors in modulating GABA release and Ca2+ influx due to KCl (10 mM) depolarization, but SK&F 97541 is more potent than (-)baclofen in modulating both Ca2+ influx and GABA release. Thus, activation of GABAB receptors by either SK&F97541 (10 microM) or by (-)baclofen (100 microM) caused about 18% inhibition of the increase in [Ca2+]i, due to KCl depolarization, and inhibited the [3H]GABA release by about 30%. The pharmacological similarities of the GABAB receptor activation in producing inhibition of both calcium channel mediated influx of Ca2+ and transmitter release suggest that presynaptic inhibition of GABA release by GABAB receptor activation may result, at least in part, from inhibition of Ca2+ influx through P-type (or possibly Q-type) Ca2+ channels, sensitive to omega-Agatoxin IVA (200 nM). Furthermore, modulation of GABA release of GABAB receptors was abolished by preincubation with pertussis toxin, suggesting that a pertussis toxin sensitive G protein may be the coupling factor between GABAB receptors and the voltage-dependent Ca2+ channels associated with the exocytotic release of GABA in rat cerebrocortical nerve terminals.

Animals↗

PubMed1996

Tolbutamide blocks Ca(2+)- and voltage-dependent K+ currents of hippocampal Ca1 neurons.

In current-clamp recordings with KMeSO4 electrodes (either whole-cell or intracellular), though tolbutamide (0.5-1 mM) did not change the resting potential, it increased both input resistance (by 12 +/- 3.8%) and spontaneous firing, and spikes were evoked by smaller depolarizing pulses. Tolbutamide reduced in a dose-dependent manner both components of post-burst afterhyperpolarizations: IC50 was 0.15 mM for medium afterhyperpolarizations and 0.33 mM for slow afterhyperpolarizations. In whole-cell recordings under voltage-clamp, 0.5-1 mM tolbutamide depressed slow outward currents by 65 +/- 5.3%. The tolbutamide-sensitive current was Ca(2+)-dependent-tolbutamide being ineffective in Mn2+, low Ca(2+)-containing medium-though tolbutamide did not significantly depress high voltage-activated Ca2+ currents. Tolbutamide reduced C-type outward currents by 45 +/- 5.9% and M-type current inward relaxations by 41 +/- 12.9%, as well as Q-type current inward relaxations by 22 +/- 5.7%. Glyburide (10 microM) did not depress afterhyperpolarizations or outward currents, even in recordings with electrodes containing 1 mM guanosine diphosphate. We conclude that the most prominent effects of 0.5-1 mM tolbutamide on CA1 neurons are caused by suppression of Ca(2+)-and voltage-dependent outward currents, including IAHP, IC and IM.

Animals↗

PubMed1995

Complete and reversible block by omega-grammotoxin SIA of glutamatergic synaptic transmission between cultured rat hippocampal neurons.

omega-Grammotoxin SIA (omega-GsTx SIA), a peptide isolated from tarantula venom, inhibits synaptosomal Ca2+ influx and neurotransmitter release, and blocks N-, P-, and Q-type voltage-gated Ca2+ channels. The whole-cell patch-clamp was used to record glutamatergic excitatory post-synaptic currents (EPSCs) evoked by extracellular stimulation of presynaptic neurons in primary rat hippocampal cultures. EPSCs displayed rapid kinetics and were blocked by CNQX. omega-Conotoxin (1 microM) GVIA inhibited EPSCs by 46%, while 30 nM and 1 microM omega-agatoxin IVA produced 12% and 69% inhibition, respectively, consistent with coupling of N-, P- and Q-type Ca2+ channels to glutamatergic synaptic transmission. omega-GsTx SIA (1 microM) rapidly, completely, and reversibly blocked glutamatergic EPSCs, but did not affect currents evoked by bath application of kainate. Thus, omega-GsTx SIA blocks glutamatergic synaptic transmission by blocking presynaptic voltage-gated Ca2+ channels. omega-GsTx SIA is the only agent that blocks selectively and reversibly the Ca2+ channels coupled to glutamate release. omega-GsTx SIA provides a unique and powerful tool for experiments requiring recovery of function following presynaptic block of synaptic transmission.

Animals↗

PubMed1995

Solution structure of omega-conotoxin MVIIC determined by NMR.

The solution structure of the P- and Q-type Ca2+ channel blocker, omega-conotoxin MVIIC (a peptidic neurotoxin composed of 26 amino acid residues), has been determined by 1H-NMR and simulated annealing calculations. The resulting calculated structures converged very well to a conformation with an average value of pairwised RMSD for N, C alpha and C' of 0.62 A. Lys-25 is buried in the molecule and less flexible so that among the four Lys residues, its side chain provides the lowest reactivity on biotinylation and the mono-biotinylation in this residue less influences the biological activity.

Amino Acid Sequence↗

PubMed1995

Dihydropyridines, phenylalkylamines and benzothiazepines block N-, P/Q- and R-type calcium currents.

We compared the effects of representative members of three major classes of cardiac L-type channel antagonists, i.e. dihydropyridines (DHPs), phenylalkylamines (PAAs) and benzothiazepines (BTZs) on high-voltage-activated (HVA) Ca2+ channel currents recorded from a holding potential of -100 mV in rat ventricular cells, mouse sensory neurons and rat motoneurons. Nimodipine (DHP), verapamil (PAA) and diltiazem (BTZ) block the cardiac L-type Ca2+ channel current (EC50: 1 microM, 4 microM and 40 microM, respectively). At these concentrations, the drugs could also inhibit HVA Ca2+ channel currents in both sensory and motor neurons. Large blocking effects (> 50%) could be observed at 2-10 times these concentrations. The omega -conotoxin-GVIA-sensitive (omega -CTx-GVIA, N-type), omega -agatoxin-IVA-sensitive (omega -Aga-IVA, P- and Q-types) and non-L-type omega -CTx-GVIA-, omega -Aga-IVA-insensitive (R-types) currents accounted for more than 90% of the global current. Furthermore, our data showed that omega -CTx-GVIA and omega -Aga-IVA spare L-type currents and have only additive blocking effects on neuronal HVA currents. We conclude that DHPs, PAAs and BTZs have substantial inhibitory effects on neuronal non-L-type Ca2+ channels. Inhibitions occur at concentrations that are not maximally active on cardiac L-type Ca2+ channels.

Animals↗

PubMed1995

Block of non-L-, non-N-type Ca2+ channels in rat insulinoma RINm5F cells by omega-agatoxin IVA and omega-conotoxin MVIIC.

The high-voltage-activated (HVA) Ba2+ currents of rat insulinoma RINm5F cells insensitive to dihydropyridines (DHP) and omega-conotoxin GVIA (omega-CTx-GVIA) have been studied for their sensitivity to omega-agatoxin-IVA (omega-Aga-IVA) and omega-CTx-MVIIC. Blockade of HVA currents by omega-Aga-IVA was partial (mean 24%), reversible and saturated around 350 nM (half block approximately 60 nM). Blockade by omega-CTx-MVIIC was more potent (mean 45%), partly irreversible and saturated above 3 microM. The effects of both toxins were additive with that of nifedipine (5 microM) and were more pronounced at positive potentials. omega-Aga-IVA action was additive with that of omega-CTx-GVIA (3 microM) but was largely prevented by cell pre-treatment with omega-CTx-MVIIC (3 microM). In contrast, omega-CTx-MVIIC block was attenuated by omega-CTx-GVIA treatment (approximately 15%), suggesting that omega-CTx-MVIIC blocks the N-type (approximately 15%) and the non-L-, non-N-type channel sensitive to omega-Aga-IVA (approximately 30%). Consistent with this, cells deprived of most non-L-type channels by pre-incubation with omega-CTx-GVIA and omega-CTx-MVIIC exhibited predominant L-type currents that activated at more negative potentials than in normal cells (-30 mV in 5 mM Ba2+) and were effectively depressed by nifedipine (maximal block of 95% from -30 mV to +40 mV). Our results suggest that, besides L- and N-type channels, insulin-secreting RINm5F cells possess also a non-L-, non-N-type channel that contributes significantly to the total current (approximately 30%). Although the pharmacology of this channel is similar to Q-type and alpha 1 class A channels, its range of activation (> -20 mV) and its slow inactivation time course resemble more that of N- and P-type channels. The channel is therefore referred to as "Q-like".

Animals↗

PubMed1996

Calcium channel types contributing to excitatory and inhibitory synaptic transmission between individual hypothalamic neurons.

The contribution of L-, N-, P- and Q-type Ca2+ channels to excitatory and inhibitory synaptic transmission and to whole-cell Ba2+ currents through Ca2+ channels (Ba2+ currents) was investigated in rat hypothalamic neurons grown in dissociated cell culture. Excitatory and inhibitory postsynaptic currents (EPSCs and IPSCs) were evoked by stimulating individual neurons under whole-cell patch-clamp conditions. The different types of high-voltage-activated (HVA) Ca2+ channels were identified using nifedipine, omega-Conus geographus toxin VIA (omega-CTx GVIA), omega-Agelenopsis aperta toxin IVA (omega-Aga IVA), and omega-Conus magus toxin VIIC (omega-CTx MVIIC). N-, but not P- or Q-type Ca2+ channels contributed to excitatory as well as inhibitory synaptic transmission together with Ca2+ channels resistant to the aforementioned Ca2+ channel blockers (resistant Ca2+ channels). Reduction of postsynaptic current (PSC) amplitudes by N-type Ca2+ channel blockers was significantly stronger for IPSCs than for EPSCs. In most neurons whole-cell Ba2+ currents were carried by L-type Ca2+ channels and by at least two other Ca2+ channel types, one of which is probably of the Q-type and the others are resistant Ca2+ channels. These results indicate a different contribution of the various Ca2+ channel types to excitatory and inhibitory synaptic transmission and to whole-cell currents in these neurons and suggest different functional roles for the distinct Ca2+ channel types.

Animals↗

PubMed1996

Re-evaluation of the P/Q Ca2+ channel components of Ba2+ currents in bovine chromaffin cells superfused with solutions containing low and high Ba2+ concentrations.

This study was undertaken to reassess the set of voltage-dependent Ca2+ channel subtypes expressed by bovine adrenal chromaffin cells maintained in primary cultures. Previous views on the pharmacology of such channels had to be revised in the light of the novel data which arose from the use in this study of low and high micromolar concentrations of omega-agatoxin IVA, and low (2 mM) and high (10 mM) concentrations of the charge carrier Ba2+. Whole-cell Ba2+ currents (IBa) through Ca2+ channels were elicited in voltage-clamped chromaffin cells, with a holding potential of -80 mV and depolarising pulses to 0 mV. Mean peak IBa was 425 pA in 2 mM Ba2+ (59 cells) and 787 pA in 10 mM Ba2+ (42 cells). In 2 mM Ba2+, omega-conotoxin MVIIC (3 microM) inhibited IBa by 79%; in 10 mM Ba2+, the blockade developed much more slowly and reached only 44%. A low concentration of omega-agatoxin IVA (20 nM) inhibited IBa by 9%; 2 microM inhibited IBa by 60%. This blockade was similar in low and high Ba2+ concentrations. After giving furnidipine (3 microM) and omega-conotoxin GVIA (1 microM), 2 microM omega-agatoxin IVA inhibited the remaining current (about 40-45%); this blockade was independent of the Ba2+ concentration. The current could be fully blocked by the cocktail furnidipine/omega-conotoxin GVIA/high omega-agatoxin IVA, both in low and high Ba2+ concentrations. The large Q-type channel component of IBa is blocked by micromolar concentrations of omega-agatoxin IVA and omega-conotoxin MVIIC. While solutions with a high Ba2+ concentration strongly delayed the development of blockade by omega-conotoxin MVIIC, the blockade by high concentrations of omega-agatoxin IVA was equally effective in solutions with a low or a high Ba2+ concentration. Hence, the use of appropriate Ba2+ and toxin concentrations in this study reveals that P-type Ca2+ channels are poorly expressed in bovine chromaffin cells; in contrast, a robust component of the current depends on Q-type Ca2+ channels. An R-type residual current is not present in these cells.

Adrenal Medulla↗

PubMed1995

Relation of [Ca2+]i to dopamine release in striatal synaptosomes: role of Ca2+ channels.

We compared the effects of KCl and 4-aminopyridine (4-AP) stimulation on the coupling of Ca2+ channel activation to [3H]dopamine ([3H]DA) release in rat striatal synaptosomes and used specific Ca2+ channel blockers to discriminate between the different VSCC's activated by the two stimulatory agents. We found that whereas [3H]DA release is strictly Ca(2+)-dependent in the case of KCl depolarization, 4-AP, at concentrations above 100 microM, progressively causes a large Ca(2+)-independent release of [3H]DA. Thus, at 1 to 3 mM 4-AP, as much as 80-95% of the [3H]DA release is Ca(2+)-independent and can be partially blocked by nomifensine, indicating that some [3H]DA release is occurring through reversal of the DA carrier. Therefore, in the studies relating [Ca2+]i to [3H]DA release we selected 4-AP concentrations lower than 100 microM and corrected for the Ca(2+)-independent release. Under these conditions, we determined that: (1) Ca2+ entry through N-type VSCC's is involved in [3H]DA release both in the case of KCl depolarization (35% inhibition by omega-CgTx) and in 4-AP stimulation (23% inhibition by omega-CgTx); (2) Ca2+ entering through P-type and/or Q-type VSCC's is also involved in [3H]DA release due to 4-AP stimulation (26% inhibition by 200 nM omega-Aga IVA); (3) Neomycin (0.35 mM) inhibited the [3H]DA release due to 4-AP stimulation by about 20% and decreased the KCl induced [3H]DA release by 55%; the effects of neomycin (0.35 mM) and omega-CgTx were additive in both cases, indicating that, at this concentration, the antibiotic does not affect significantly N-type Ca2+ channels; (4) When applied together, omega-CgTx and omega-Aga IVA inhibited the 4-AP stimulated [3H]DA release by about 40-50%, suggesting that the remaining large fraction of the VSCC's activated by 4-AP stimulation are non-N, non-P VSCC's and are coupled to Ca(2+)-dependent [3H]DA release; (5) The contribution of L-type VSCC's is uncertain, since there seemed to be a small contribution in the case of KCl depolarization, but not in the case of 4-AP stimulation. On the whole, the results suggest that the release of [3H]DA in the rat striatal nerve terminals depends on Ca2+ entry through N-, P-, possibly Q-, and other non-N-, non-P-type VSCC's when either KCl or 4-AP stimulation is utilized.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Antibodies to recombinant synaptotagmin and calcium channel subtypes in Lambert-Eaton myasthenic syndrome.

Several proteins have been postulated as possible targets of immune attack in Lambert-Eaton myasthenic syndrome (LEMS). Heterogeneity of autoantibodies in sera from 20 LEMS patients was studied by comparing their reactivity to synaptotagmin, a synaptic vesicle protein, and voltage-gated calcium channels (VGCCs). Six patients' sera (1 with small cell lung carcinoma (SCLC)) contained antibodies specifically recognizing the recombinant synaptotagmin on immunoblots. Thirteen (11 with SCLC) and 16 (11 with SCLC and 1 with poorly differentiated cell carcinoma in the lung) patients' sera immunoprecipitated omega-conotoxin GVIA-labeled N-type and omega-conotoxin MVIIC-labeled Q-type VGCCs, respectively. Three of 6 synaptotagmin-positive sera had cross-reactivity with N and/or Q subtypes of VGCC; the remaining 3 showed no cross-reactivity with VGCCs. Results indicate that LEMS sera are heterogeneous in the spectrum of containing antibodies, and suggest that this heterogeneity reflects the immune response to various synaptic proteins including not only multiple VGCCs but also synaptosecretory complex proteins.

Adult↗

PubMed1995

Alpha-1 subunits of voltage gated Ca2+ channels in the mesencephalon x neuroblastoma hybrid cell line MES23.5.

The identity of alpha 1 subunits from voltage operated Ca2+ channels was determined in the rat/mouse mesencephalon x N18TG2 hybridoma cell line MES23.5, by sequence analysis of reverse transcription-polymerase chain reaction products and antagonist binding. Sequences were derived from the L-(alpha 1D), Q-(alpha 1A) and omega-conotoxin GVIA sensitive N-type (alpha 1B) Ca2+ channel alpha 1 subunits. The amplified fragments, which are homologous to the region between domain III and IV of known alpha 1 subunits, reveal splice variation in the L- and Q-type alpha 1 subunit of MES23.5 cells. The transcripts of alpha 1 subunits in these cells were quantified by RNAase protection assay. The data show the existence of different Ca2+ channel types in a single cell line and may reflect multiple functions of voltage operated Ca2+ channels during growth, differentiation and transmitter release.

Amino Acid Sequence↗

PubMed1995

Diversity of voltage-gated calcium currents in large diameter embryonic mouse sensory neurons.

Voltage-gated Ca2+ currents were investigated in a subpopulation of dorsal root ganglion neurons (large diameter, neurofilament-positive) acutely isolated from 13-day-old mouse embryos and recorded using the whole-cell patch-clamp technique. Low- and high-voltage-activated calcium currents were recorded. These currents could be identified and separated by their distinct (i) threshold of activation, (ii) ability to run-up during the early phase of recording and (iii) decay kinetics using Ba2+ instead of Ca2+ as the charge carrier. Among high-voltage-activated currents, L-, N- and P-type Ca2+ currents were identified by their sensitivity to, respectively, the dihydropyridine agonist Bay K 8644 (5 microM) and antagonist nitrendipine (3 microM), omega-conotoxin GVIA (3 microM) and omega-agatoxin IVA (30 nM). In the combined presence of nitrendipine (3 microM), omega-conotoxin GVIA (3 microM) and omega-agatoxin IVA (30 nM), two additional high-voltage-activated components were detected. One, blocked by 500 nM omega-conotoxin MVIIC and 1 microM omega-agatoxin IVA, had properties similar to those of the Q-type Ca2+ current first reported in cerebellar granule cells. The other, defined by its resistance to saturating concentrations of all the blockers mentioned above applied in combination, resembles the R-type Ca2+ current also described in cerebellar granule cells. In conclusion, embryonic sensory neurons appear to express a large repertoire of voltage-activated Ca2+ currents with distinct pharmacological properties. This diversity suggests a great variety of pathways for Ca2+ signaling which may support different functions during development.

Animals↗

PubMed1996

Voltage-sensitive Ca2+ channels involved in nicotinic receptor-mediated [3H]dopamine release from rat striatal synaptosomes.

The potent nicotinic agonist anatoxin-a elicits mecamylamine-sensitive [3H]dopamine release from striatal synaptosomes, and this action is both Na+ and Ca2+ dependent and is blocked by Cd2+. This suggests that stimulation of presynaptic nicotinic receptors results in Na+ influx and local depolarisation that activates voltage-sensitive Ca2+ channels, which in turn provide the Ca2+ for exocytosis. Here we have investigated the subtypes of Ca2+ channels implicated in this mechanism. [3H]-Dopamine release evoked by anatoxin-a (1 microM) was partially blocked by 20 microM nifedipine, whereas KCl-evoked release was insensitive to the dihydropyridine. However, a 86Rb+ efflux assay of nicotinic receptor function suggested that nifedipine has a direct effect on the receptor, discrediting the involvement of L-type channels. The N-type Ca2+ channel blocker omega-conotoxin GVIA (1 microM) blocked anatoxin-a-evoked [3H]dopamine release by 60% but had no significant effect on 86Rb+ efflux; release evoked by both 15 and 25 mM KCl was inhibited by only 30%. The P-type channel blocker omega-agatoxin IVA (90 nM) also inhibited KCl-evoked release by approximately 30%, whereas anatoxin-a-evoked release was insensitive. The Q-type channel blocker omega-conotoxin MVIIC (1 microM) had no effect on either stimulus. These results suggest that presynaptic nicotinic receptors on striatal nerve terminals promote [3H]dopamine release by activation of N-type Ca2+ channels. In contrast, KCl-evoked [3H]dopamine release appears to involve both N-type and P-type channels.

Animals↗

PubMed1995

Regional difference of high voltage-activated Ca2+ channels in rat CNS neurones.

The diversity of high voltage-activated (HVA) Ca2+ channels in rat CNS neurones was investigated with the nystatin perforated patch recording configuration. The neurones were freshly dissociated from rat substantia nigra, ventromedial hypothalamus, tuberomammillary nucleus, nucleus tractus solitarius, hippocampal CA1 region and cerebellum. Five different types of HVA Ca2+ channels were distinguished pharmacologically; dihydropyridine sensitive L-type, omega-conotoxin-GVIA sensitive N-type, omega-agatoxin-IVA sensitive P-type, omega-conotoxin-MVIIC sensitive Q-type, and R-type which is insensitive to these organic Ca2+ antagonists. The results showed clearly that the five subtypes of HVA Ca2+ channels differ considerably in their distribution among various CNS regions.

Animals↗

PubMed1995

Two types of calcium channels sensitive to omega-agatoxin- TK in cultured rat hippocampal neurones.

We characterized the electrophysiological properties of calcium channels in cultured rat hippocampal neurones using omega-agatoxin-TK (omega-Aga-TK) and compared them with those of the P-type channel and the BI (alpha 1A) channel which resembles the Q-type channel. Two types of omega-Aga-TK-sensitive calcium channels were detected in hippocampal neurones. The first type showed slow inactivation, high sensitivity to omega-Aga-TK and low reversibility from omega-Aga-TK-induced block, resembling the P-type channel. The second type showed fast inactivation, low sensitivity to omega-Aga-TK and high reversibility from omega-Aga-TK-induced block. These results suggest that the second type of calcium channel (Q-type-like) plays a prominent role in the hippocampal synaptic transmission.

Agatoxins↗

PubMed1989

Anoxia on slow inward currents of immature hippocampal neurons.

1. The effects of brief anoxia (2-4 min) on membrane currents--especially the tetrodotoxin (TTX)-insensitive, Cd2+-sensitive slow inward currents, presumed to be Ca2+ currents--were studied by single-electrode voltage clamp in CA1 and CA3 neurons in submerged hippocampal slices from adult and newborn Wistar rats (PN1-13). 2. In mature neurons, anoxia had no effect on Q-type inward relaxations, but slowly activating C-type outward currents were depressed. The most striking change was the suppression of Ca inward currents (especially the slowly inactivating L-type, by greater than 95%). This effect of anoxia was not sensitive to the N-methyl-D-aspartate (NMDA) receptor blocker, D-aminophosphonovalerate. Anoxia also reversibly abolished the NMDA-evoked inward current. 3. In neurons from newborn animals (PN1-6), Q-type inward relaxations and postanoxic outward currents were very small or undetectable. The slow inward (Ca) currents were smaller than in mature cells, but they showed a clearer separation between low-threshold, fast-inactivating and high-threshold, slowly inactivating currents. Both types of current were more resistant to anoxia (mean depression of L-type was by only 53.3 +/- 5.6%, mean +/- SE). 4. In such immature neurons, the NMDA-evoked inward currents were also more resistant to anoxia. 5. By PN7-13, increasing maturation was reflected in 1) larger voltage-dependent inward currents, 2) increasingly evident Q-type relaxations and postanoxic outward currents, and 3) near-complete blockade of inward currents by anoxia (at PN11-13, mean depression of L-type currents was by 98.5 +/- 1.5%).

Aging↗

PubMed1996

Pituitary adenylate cyclase-activating polypeptide causes rapid Ca2+ release from intracellular stores and long lasting Ca2+ influx mediated by Na+ influx-dependent membrane depolarization in bovine adrenal chromaffin cells.

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been reported to increase intracellular Ca2+ concentrations ([Ca2+]i) and catecholamine release in adrenal chromaffin cells. We measured [Ca2+]i with fura-2 and recorded ion currents and membrane potentials with the whole cell configuration of the patch-clamp technique to elucidate the mechanism of PACAP-induced [Ca2+]i increase in bovine adrenal chromaffin cells. PACAP caused [Ca2+]i to increase due to Ca2+ release and Ca2+ influx, and this was accompanied by membrane depolarization and inward currents. The Ca2+ release was suppressed by ryanodine, an inhibitor of caffeine-sensitive Ca2+ stores, but was unaffected by cinnarizine, an inhibitor of inositol trisphosphate-induced Ca2+ release. Ca2+ influx and inward currents were both inhibited by replacement of extracellular Na+, and Ca2+ influx was inhibited by nicardipine, an L-type Ca2+ channel blocker, or by staurosporine, a protein kinase C (PKC) inhibitor, but was unaffected by a combination of omega- conotoxin-GVIA, omega-agatoxin-IVA, and omega-conotoxin- MVIIC, blockers of N-, P-, and Q-type Ca2+ channels. Moreover, 1-oleoyl-2-acetyl-sn-glycerol, a PKC activator, induced inward currents and Ca2+ influx. These results indicate that PACAP causes both Ca2+ release, mainly from caffeine-sensitive Ca2+ stores, and Ca2+ influx via L-type Ca2+ channels activated by membrane depolarization that depends on PKC-mediated Na+ influx.

Adrenal Glands↗