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PubMed1998

[Views on the use of calcium channel blockers in the treatment of heart ischemia and hypertension].

Calcium-channel blockers differ in their molecular structure, their sites and modes of action. Based on rapport's about short acting calcium-channel blockers, several recent publications have questioned the safety of agents in this class, particularly nifedypine. It has been well documented that nifedypine can cause a precipitation uncontrollable drop in arterial blood pressure, which can be dangerous in the presence of ischemic heart disease, hypertension and other hemodynamically unstable situation. The cardiovascular risk for patients prescribed short-acting calcium channel blockers was eight times than for those taking, long-acting ones. Sustained-release preparations are the preferred form of therapy, as they appear, to be safer than short-acting agents. Most calcium-channel blockers, including verapamil, diltiazem, amlodypine, felodipine, nitrendipine and nicardipine have been shown to be effective in reducing symptoms of myocardial ischemia, and all have been used successfully for lowering blood pressure in hypertensive patients. Data from trials of nondihydropyridines have not demonstrated increased mortality or myocardial infarction rates in patients with myocardial ischemia and good left ventricular function. In patients with coronary artery disease and in hypertensive patients with poor left ventricular function, amlodypine or felodipine may be relatively safe alternative. Particular attention should be paid to the benefits of werapamil in postinfarct patients. In patients with hypertension, calcium-channel blockers should be reserved for use when diuretics, beta-blockers or angiotensin-converting enzyme inhibitors have been used already or contraindicated or are not tolerated and when further blood pressure reduction is necessary.

Aged↗

PubMed2002

Expression of the L-type calcium channel in human heart failure.

L-type calcium channels play an important role in excitation-contraction coupling. After cardiomyocyte depolarization L-type calcium channels open and Ca2+ ions enter the cell. These small Ca2+ inward currents trigger calcium release from the junctional sarcoplasmic reticulum, a process called calcium-induced calcium release. Subsequently, the cytosolic Ca2+ concentration rises rapidly to levels that initiate contraction. In heart failure calcium-induced calcium release is disturbed, and in this review we focus on the L-type calcium channel and its contribution to this defective excitation-contraction coupling.

Animals↗

PubMed2001

Calcium channels coupled to neurotransmitter release at dually innervated neuromuscular junctions in the newborn rat.

We studied the effect of several calcium channel blockers (omega-Conotoxin-GVIA, 1 and 3microM; omega-Agatoxin-IVA, 100nM; Nitrendipine, 1 and 10microM) on evoked transmitter release at singly and dually innervated endplates of the levator auris longus muscle from three- to six-day-old rats. In dually innervated fibers, a second endplate potential may appear after the first one when we increase the stimulation intensity. The lowest and highest endplate potential amplitudes are designated "small endplate potential" and "large endplate potential", respectively. The percentage of doubly innervated junctions remains almost constant throughout the age range examined. Nevertheless, the percentage of junctions innervated by three or more terminal axons drops, whereas the singly innervated junctions increase. Therefore, between postnatal days 3 and 6, roughly half the neuromuscular junctions may experience the final process of axonal elimination. The synaptic efficacy of the large endplate potential in dual junctions, measured as the mean amplitude of the synaptic potential and mean quantal content, was the same as in the junctions that had become recently mono-innervated in the same postnatal period. In singly innervated fibers, the endplate potential size was strongly reduced by both the P/Q-type voltage-dependent calcium channel blocker omega-Agatoxin-IVA (79.17+/-4.02%; P < 0.05) and the N-type voltage-dependent calcium channel blocker omega-Conotoxin-GVIA (56.31+/-7.80%; P < 0.05), whereas endplate potential amplitude was not significantly changed by the L-type voltage-dependent calcium channel blocker Nitrendipine. In dually innervated fibers, the P/Q-type voltage-dependent calcium channel blocker omega-Agatoxin-IVA and L-type voltage-dependent calcium channel blocker Nitrendipine increased the size of the small endplate potential (161.29+/-47.87% and 109.32+/-11.03%, respectively; P < 0.05 in both cases) and reduced the large endplate potential (74.42+/-15.32% and 70.91+/-10.04%, respectively; P < 0.05 in both cases). The N-type voltage-dependent calcium channel blocker omega-Conotoxin-GVIA significantly increased the small endplate potential in the first few minutes after toxin application (at 10min: 90.23+/-17.38%; P < 0.05). This increase was not maintained, while the large endplate potential was strongly inhibited (69.25+/-7.5%; P < 0.05). In conclusion, in the dually innervated endplates of the newborn rat, presynaptic calcium channel types can have different roles in transmitter release from each of the two inputs, which suggests that nerve terminal voltage-dependent calcium channels are involved in neonatal synaptic maturation.

Aging↗

PubMed1990

Dihydropyridine-sensitive single calcium channels in airway smooth muscle cells.

We have identified and characterized single voltage-dependent calcium channels in both acutely dissociated rat bronchial and cultured human tracheobronchial smooth muscle cells using the patch-clamp technique. In both cell types, on-cell membrane patches displayed unitary currents selective for barium ions and exhibited one conductance level (21-26 pS), and the open state probability was increased by membrane depolarization. Unitary barium currents were enhanced by the calcium channel selective agonist, BAY R 5417, and inhibited by the dihydropyridine calcium channel antagonist, nisoldipine (apparent inhibition constant less than 100 nM). Moreover, the degree of nisoldipine inhibition of the rat bronchial smooth muscle channels was increased with membrane depolarization in a manner consistent with the drug interacting with highest affinity to the inactivated channel state. In addition, the sensitivity to BAY R 5417 augmentation and nisoldipine inhibition of depolarization-induced tonic force of intact rat bronchial ring segments was in close agreement to the single channel results. Thus these data suggest that activation of voltage-dependent calcium channels can influence airway contraction and that dihydropyridines may be effective modulators of depolarization-induced increases in bronchial tone. We conclude that both rat and human airway smooth muscle cells have high-conductance voltage-dependent calcium channels that interact in a predictable manner with dihydropyridines and are similar to voltage-dependent calcium channels observed in other smooth muscle cells.

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

PubMed2000

Sustained activation of hippocampal Lp-type voltage-gated calcium channels by tetanic stimulation.

The molecular heterogeneity of voltage-gated calcium channels is mirrored by extensive biophysical diversity. Subtype-selective antagonists have been used to place different kinds of calcium channels in functional categories. Dihydropyridine (DHP) antagonists have been used, for example, to implicate L-type calcium channels in the induction of NMDA receptor-independent forms of synaptic plasticity. DHPs, however, do not discriminate between the recently identified Lp and Ls subtypes of L-type calcium channel. The different properties of the two kinds of L-type channels suggest that they may have different functional roles. Ls channels are comparable with cardiac L-type channels, whereas Lp channels show low-threshold voltage-dependent potentiation. To clarify the potential roles of Lp and Ls channels in the induction of synaptic plasticity, we studied the responses of these channels to trains of action potentials. The frequency and duration of the trains were chosen to mimic the stimuli used to induce changes in synaptic strength. Cell-attached single-channel recordings from cultured hippocampal neurons revealed that both Lp and Ls channels responded to these trains, but only Lp channels showed persistent activation that outlasted the train. The magnitude of Lp channel activity increased with increasing action potential frequency and train duration. Stimuli that reproduced the postsynaptic response to action potential trains were also examined, and Lp channels were found to show much greater responses than were Ls channels. These results suggest that the Lp channel may play a critical role in the induction of long-lasting changes in synaptic strength.

Action Potentials↗

PubMed1990

Yawning induced by apomorphine, physostigmine or pilocarpine is potentiated by dihydropyridine calcium channel blockers.

Previous studies have shown that dihydropyridine (DHP) calcium channel blockers can potentiate yawning induced by apomorphine in rats. The present study was undertaken to examine whether or not this interaction was seen with other compounds that induce yawning or if it represented a specific interaction with dopaminergic mechanisms. Yawning induced by apomorphine (40 micrograms/kg SC), physostigmine (50 micrograms/kg SC) or pilocarpine (1 mg/kg SC) was dose-dependently potentiated by the DHP calcium channel blocker nifedipine (1.25-10 mg/kg IP). Nimodipine (1.25-5 mg/kg IP) and nitrendipine (1.25-5 mg/kg IP) also significantly increased the yawning response. The DHP calcium channel blockers alone induced only a low incidence of yawning. The effects of nifedipine on physostigmine-induced yawning were reversed by the DHP calcium channel activator BAY K 8644 which also inhibited yawning induced by physostigmine (100 micrograms/kg SC) and pilocarpine (2 mg/kg SC). In contrast to the DHP compounds, diltiazem (2.5-10 mg/kg IP) and verapamil (2.5-10 mg/kg IP) failed to potentiate yawning. Sulpiride (10 mg/kg SC) antagonised the nifedipine potentiation of apomorphine-induced yawning but not that of physostigmine-induced yawning; atropine (2.5 mg/kg SC) antagonised both effects. These results support the hypothesis that this effect of dihydropyridine compounds is not dependent on, nor mediated through, dopaminergic mechanisms.

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

PubMed1999

Modulation of neuronal voltage-gated calcium channels by farnesol.

The modulation of presynaptic voltage-dependent calcium channels by classical second messenger molecules such as protein kinase C and G protein betagamma subunits is well established and considered a key factor for the regulation of neurotransmitter release. However, little is known of other endogenous mechanisms that control the activity of these channels. Here, we demonstrate a unique modulation of N-type calcium channels by farnesol, a dephosphorylated intermediate of the mammalian mevalonate pathway. At micromolar concentrations, farnesol acts as a relatively non-discriminatory rapid open channel blocker of all types of high voltage-activated calcium channels, with a mild specificity for L-type channels. However, at 250 nM, farnesol induces an N-type channel-specific hyperpolarizing shift in channel availability that results in approximately 50% inhibition at a typical neuronal resting potential. Additional experiments demonstrated the presence of farnesol in the brain (rodents and humans) at physiologically relevant concentrations (100-800 pmol/g (wet weight)). Altogether, our results indicate that farnesol is a selective, high affinity inhibitor of N-type Ca(2+) channels and raise the possibility that endogenous farnesol and the mevalonate pathway are implicated in neurotransmitter release through regulation of presynaptic voltage-gated Ca(2+) channels.

Calcium Channel Blockers↗

PubMed1991

Reduced calcium sensitivity of dihydropyridine binding to calcium channels in spontaneously hypertensive rats.

To explore the role of calcium channels in hypertension, dihydropyridine ([3H]PN200-110) binding to heart, brain, and skeletal muscle microsomes of 4-, 8- and 15-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats was measured. At a constant Ca2+ ion concentration (pCa 3.0), maximal binding (Bmax) of dihydropyridine binding to heart and brain microsomes was significantly enhanced in 8- and 15-week-old SHR compared with WKY rats (p less than 0.01), whereas this phenomenon was not observed in 4-week-old SHR and WKY rats. Bmax and dissociation constant (Kd) values for skeletal muscle microsomes from SHR showed no difference compared with WKY rats irrespective of age. Dihydropyridine binding to heart microsomes, brain microsomes, and solubilized skeletal muscle microsomes exhibited strong calcium dependence. The Ca2(+)-dependent dihydropyridine binding curves for heart showed a Hill slope, and pK 0.5 values for 15-week-old SHR and WKY rats were 0.70 +/- 0.12 and 4.66 +/- 0.12 versus 0.72 +/- 0.12 and 5.66 +/- 0.08 (n = 4, mean +/- SD), respectively, indicating that 15-week-old SHR require 10-fold higher calcium concentration than WKY rats to promote dihydropyridine binding. The pK 0.5 values of calcium for brain and solubilized skeletal muscle calcium channels in 15-week-old SHR were also significantly lower than in WKY rats. This difference first became apparent in SHR and WKY rats as early as 4 and 8 weeks after birth. These results suggest that enhancement of calcium channel density might occur in the heart and brain of SHR in response to elevated blood pressure and that reduced calcium sensitivity of dihydropyridine binding to calcium channels might be a primary characteristic of this rat strain.

Animals↗

PubMed1998

A mutation affecting dihydropyridine-sensitive current levels and activation kinetics in Drosophila muscle and mammalian heart calcium channels.

The Dmca1D gene encodes a Drosophila calcium channel alpha1 subunit. We describe the first functional characterization of a mutation in this gene. This alpha1 subunit mediates the dihydropyridine-sensitive calcium channel current in larval muscle but does not contribute to the amiloride-sensitive current in that tissue. A mutation, which changes a highly conserved Cys to Tyr in transmembrane domain IS1, identifies a residue important for channel function not only in Drosophila muscle but also in mammalian cardiac channels. In both cases, mutations in this Cys residue slow channel activation and reduce expressed currents. Amino acid substitutions at this Cys position in the cardiac alpha1 subunit show that the size of the side chain, rather than its ability to form disulfide bonds, affects channel activation.

Amiloride↗

PubMed2004

[Dosage and specificity of anti-calcium channel antibodies in Lambert-Eaton myasthenic syndrome].

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune channelopathy in which patients produce autoantibodies directed against voltage-gated calcium channels. Autoantibodies down-regulate calcium channels resulting in reduced transmitter release, which in turn leads to muscular weakness and autonomic dysfunction. LEMS is paraneoplastic in 60-70% of patients, most frequently associated with small cell lung carcinoma (SCLC). SCLC lines express many neuronal and neuroendocrine proteins including neuronal calcium channels of the Cav2 family (P/Q and N-type channels). It is thus likely that the paraneoplastic form of LEMS is the consequence of an anti-tumoral immune response and the production of antibodies that cross-react with identical or homologous antigens in nerve terminals. Neurological symptoms generally appear several Months before detection of the tumor. Consequently correct diagnosis of LEMS is crucial as it can allow early treatment of a particularly aggressive carcinoma. Based on published studies, our laboratory has set-up serological assays for LEMS autoantibodies as an aid to diagnosis. Calcium channels in detergent extracts of rat brain or cerebellum membranes were labeled with radioligands specific for N-type (125I-omega conotoxin GVIA) or P/Q-type (125I-omega conotoxin MVIIC) calcium channels. Autoantibodies that immunoprecipitate the ligand/channel complex can thus be titrated. Analysis of 31 LEMS sera revealed the presence of anti-N type channel antibodies in 58% and anti-P/Q type channel antibodies in 74% of patients with titres ranging from 90 to 2950 pM. Only 5 patients were seronegative in both tests, thus a combination of the two assays reliably detected autoantibodies in 26/31 (84%) patients.

Adolescent↗

PubMed1999

Blocking effect of puerarin on calcium channel in isolated guinea pig ventricular myocytes.

OBJECTIVE: To identify whether Puerarin (Puer) has blocking effects on L-type calcium channel. METHODS: We used whole-cell recording of patch-clamp techniques to analyse calcium channel current in ventricular myocytes isolated from Langendorff guinea pig hearts by collagenase. RESULTS: In control group, peak calcium channel current was decreased by 10.6% and 29.8% at 5, 10 min of recording time, respectively. For the same period, 0.1 mmol/L Puer reduced calcium current by 23.9% and 72.4%. 0.1 and 1 mmol/L Puer inhibited the amplitude of peak Calcium channel current by 40.6% and 63.2% after perfusing for 10 min. Compared with control group in which "rundown" phenomenon was observed, Puer also demonstrated its blocking effect on L-type channel. While washout of Puer with perfusing solution, calcium channel current went down further instead of recovery. Current-voltage (I-V) curves showed that the levels of calcium channel current were obviously decreased by Puer (both 0.1 mmo/L and 1 mmo/L) form -40 mV to +10 mV. CONCLUSION: Puer has blocking effect on L-type calcium channel in a concentration dependent manner.

Animals↗

PubMed2000

Transcriptional regulation of L-type calcium channel expression in cardiac myocytes.

The L-type calcium channel is a heteromultimeric protein complex, which is expressed in the cardiac sarcolemma. Although post-translational regulation of its subunits by protein kinase A (PKA) has been widely reported, little is known about molecular processes that regulate expression of calcium channel subunits (alpha(1C), alpha(2)- delta, and beta(2A)subunits). Previous studies from our group demonstrate that the steady-state mRNA level of the alpha(1C)unit is increased by treatment of myocytes with beta -adrenergic agonists. The current study is designed to determine whether the mRNA levels for all subunits of the L-type calcium channel are coordinately controlled by a beta -adrenergic agonist, and whether this occurs predominantly through control of rate of transcription. Nuclear run-on assays were used to determine the transcription initiation rate of these genes in cultured neonatal rat cardiac myocytes. In isoproterenol (10(-7)m)-treated myocytes, transcription of genes encoding the alpha(1C), alpha(2)- delta, and beta(2A)subunits was enhanced. The increases in transcription initiation rate for alpha(1C), alpha(2)- delta, and beta(2A)subunits genes were 404%, 367%, and 240% of control, respectively. Pretreatment with the beta -adrenergic antagonist propranolol (10(-5)m) or PKA inhibitor H-89 (10(-6)m) blocked the effects of isoproterenol, while either drug alone did not affect the gene transcription rate significantly. Steady state mRNA levels of the subunits increased following isoproterenol treatment. These results suggest that beta -adrenergic stimulation and the PKA signaling pathway play an important role in transcriptional regulation of the L-type calcium channel in myocyte. The expression of all the subunits of this ion channel is under coordinate transcriptional control.

Adrenergic beta-Agonists↗

PubMed1991

Some central pharmacological effects of the calcium channel antagonist flunarizine.

Our earlier studies showed that dihydropyridine calcium channel antagonists have some central pharmacological effects. Flunarizine is considered to be a calcium channel antagonist; therefore this study was aimed at investigating the effect of flunarizine (given in single doses of 5, 10 and 20 mg/kg p.o.) in behavioural models in which calcium channel antagonists of the dihydropyridine type were previously studied. Flunarizine inhibited the apomorphine-induced stereotypy and yawning behaviour in rats. It decreased the hypothermia induced by a low dose of apomorphine in mice, but not that one induced by high dose of it. The quinpirole-induced hypothermia was also reduced. In the tests used for evaluation of the effect on the serotonergic system, flunarizine decreased the 5-HTP-induced head twitches and partly antagonized the fenfluramine- and quipazine-induced hyperthermias (at a high ambient temperature). In the forced swimming test flunarizine was inactive in mice and rats. The obtained results indicate that flunarizine exerts central antagonistic effects on the dopaminergic and serotonergic systems and has no antidepressant activity. Flunarizine differs from calcium channel antagonists of the dihydropyridine type, which have no dopamine-antagonistic activity and show anti-depressant-like properties.

5-Hydroxytryptophan↗

PubMed1987

The effect of calcium channel blockers on blood platelet function, especially calcium uptake.

The effects of organic and inorganic calcium antagonists on washed platelets from rat and human have been studied. Platelet aggregation was assessed by turbidimetry. Endogenous serotonin release was measured on the same sample by means of electrochemically treated carbon fiber electrodes. The organic calcium antagonist, nitrendipine, and the inorganic calcium channel blockers (Co2+, Mn2+, Cd2+, La3+) drastically inhibited rat and human platelet aggregation induced by thrombin, ADP or adrenaline in the presence of 0.32 mM Ca2+. In our conditions, the thrombin-induced release of endogenous serotonin was found to be external Ca2+-dependent and completely inhibited by 20 microM nitrendipine or 1 mM Cd2+. In addition, Ba2+ or Sr2+ ions can be substituted for Ca2+ to bring about platelet aggregation as well as endogenous serotonin secretion. In Ba2+ or Sr2+-containing media, rat platelet aggregation and/or serotonin secretion can be inhibited by either nitrendipine or Cd2+. Finally, we have also studied the thrombin- and external Ca2+-dependence of radiolabeled calcium uptake by rat platelets. We found that the thrombin-induced 45Ca uptake was inhibited by either 18 microM nitrendipine or 1 mM Cd2+. These results provide strong evidence for the existence of an influx of divalent cations (Ca2+, Sr2+, Ba2+) triggering platelet function. They also suggest, although they do not prove, that the translocation of these cations occurs through an agonist-operated channel as proposed by Hallam and Rink (FEBS Lett. 186 (1986) 175-179).

Animals↗

PubMed1996

Identification of PK-A phosphorylation sites in the carboxyl terminus of L-type calcium channel alpha 1 subunits.

Full length L-type calcium channel alpha 1 subunits are rapidly phosphorylated by protein kinase A (PK-A) in vitro and in vivo at sites located in their long carboxyl terminal tails. In skeletal muscle, heart, and brain the majority of biochemically isolated alpha 1 subunits lacks these phosphorylation sites due to posttranslational proteolytic processing. Truncation may therefore modify the regulation of channel activity by PK-A. We combined site-directed mutagenesis and heterologous expression to investigate the extent to which putative cAMP-dependent phosphorylation sites in the C-terminus of alpha 1 subunits from skeletal muscle, heart, and brain are phosphorylated in vitro. The full length size form of wild-type and mutant calcium channel alpha 1 subunits was obtained at high yield after heterologous expression in Saccharomyces cerevisiae. Like in fetal rabbit myotubes [Rotman, E.I., et al. (1995) J. Biol. Chem. 270, 16371-16377], the rabbit skeletal muscle alpha 1 C-terminus was phosphorylated at serine residues 1757 and 1854. In the carboxyl terminus of alpha 1S from carp skeletal muscle and alpha 1C from rabbit heart a single serine residue was phosphorylated by PK-A in vitro. The C-terminus of alpha 1D was phosphorylated at more than one site. Employing deletion mutants, most of the phosphorylation ( > 70%) was found to occur between amino acid residues 1805 and 2072. Serine 1743 was identified as additional phosphorylation site in alpha 1D. We conclude that in class S and C calcium channels the most C-terminal phosphorylation sites are substrate for PK-A in vitro, whereas in class D calcium channels phosphorylation also occurs at a site which is likely to be retained even after posttranslational truncation.

Animals↗

PubMed2000

Expression of mRNAs for the alpha 1 subunit of voltage-gated calcium channels in human osteoblast-like cell lines and in normal human osteoblasts.

The activation of osteoblast calcium channels by many bone regulatory factors suggests an important role for intracellular calcium signaling in the control of bone remodeling. At least six different genes for the alpha 1 subunit of voltage-gated calcium channels have been cloned including L-type (alpha 1S, alpha 1C, and alpha 1D) and non-L-type (alpha 1A, alpha 1B, and alpha 1E) isoforms. The goal of the present study was to identify which of these calcium channel isoforms are transcribed in human osteoblast-like cell lines (hFOB, MG-63, SAOS-2, TE-85, G-292) and in cultures of normal human osteoblasts. Reverse transcriptase-PCR was used to amplify sequences corresponding to each of the alpha 1 subunits using isoform specific primers. The products of the PCR reaction were cloned and sequenced to verify their identify and used to probe southern blots of the PCR reactions. The results indicate that among the different types of osteoblast-like cells examined, two calcium channel isoforms were always expressed (alpha 1C and alpha 1A), three isoforms were variably expressed (alpha 1S, alpha 1D and alpha 1B), and one isoform was not expressed in any of the osteoblast-like cells (alpha 1E) but was easily detected in human brain controls. Our results indicate that mRNAs for multiple calcium channel alpha 1 subunits are expressed in human osteoblasts, including both L-type and non-L-type isoforms. In addition, significant heterogeneity exists between the different osteoblast cell models examined in the type and mRNA abundance of the different calcium channel isoforms.

Bone Neoplasms↗

PubMed2000

G-Protein types involved in calcium channel inhibition at a presynaptic nerve terminal.

The inhibition of presynaptic calcium channels via G-protein-dependent second messenger pathways is a key mechanism of transmitter release modulation. We used the calyx-type nerve terminal of the chick ciliary ganglion to examine which G-proteins are involved in the voltage-sensitive inhibition of presynaptic N-type calcium channels. Adenosine caused a prominent inhibition of the calcium current that was totally blocked by pretreatment with pertussis toxin (PTX), consistent with an exclusive involvement of G(o)/G(i) in the G-protein pathway. Immunocytochemistry was used to localize these G-protein types to the nerve terminal and its transmitter release face. We used two approaches to test for modulation by other G-protein types. First, we treated the terminals with ligands for a variety of G-protein-linked neurotransmitter receptor types that have been associated with different G-protein families. Although small inhibitory effects were observed, these could all be eliminated by PTX, indicating that in this terminal the G(i) family is the sole transmitter-induced G-protein inhibitory pathway. Second, we examined the kinetics of calcium channel inhibition by uncaging the nonselective and irreversible G-protein activator GTPgammaS, bypassing the receptors. A large fraction of the rapid GTPgammaS-induced inhibition persisted, consistent with a G(o)/G(i)-independent pathway. Immunocytochemistry identified G(q), G(11), G(12), and G(13) as potential PTX-insensitive second messengers at this terminal. Thus, our results suggest that whereas neurotransmitter-mediated calcium channel inhibition is mainly, and possibly exclusively, via G(o)/G(i), other rapid PTX-insensitive G-protein pathways exist that may involve novel, and perhaps transmitter-independent, activating mechanisms.

Adenosine↗

PubMed2003

Calcium channel alpha2delta subunits: differential expression, function, and drug binding.

Voltage-activated calcium channels are transmembrane proteins that act as transducers of electrical signals into numerous intracellular activities. On the basis of their electrophysiological properties they are classified as high- and low-voltage-activated calcium channels. High-voltage-activated calcium channels are heterooligomeric proteins consisting of a pore-forming alpha1 subunit and auxiliary alpha2delta, beta, and--in some tissues--gamma subunits. Auxiliary subunits support the membrane trafficking of the alpha1 subunit and modulate the kinetic properties of the channel. In particular, the alpha2delta subunit has been shown to modify the biophysical and pharmacological properties of the alpha1 subunit. The alpha2delta subunit is posttranslationally cleaved to form disulfide-linked alpha2 and, delta proteins, both of which are heavily glycosylated. Recently it was shown that at least four genes encode for alpha2delta subunits which are expressed in a tissue-specific manner. Their biophysical properties were characterized in coexpression studies with high- and low-voltage-activated calcium channels. Mutations in the gene encoding alpha2delta-2 have been found to underlie the ducky phenotype. This mouse mutant is a model for absence epilepsy and is characterized by spike wave seizures and cerebellar ataxia. Alpha2delta subunits can also support pharmacological interactions with drugs that are used for the treatment of epilepsy and neuropathic pain.

Acetates↗