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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous work had shown that incubation with the nicotinic antagonist d-tubocurarine resulted in a marked increase in alpha-bungarotoxin (alpha-BGT) binding in adrenal medullary chromaffin cells in culture; the possible molecular mechanisms involved in up-regulating the alpha-BGT sites were investigated. To determine whether changes in the extracellular K+ concentration could influence the number of toxin binding sites, the chromaffin cells were incubated in the presence of 2-50 mM K+; this resulted in an increase in alpha-BGT binding similar to that observed with the nicotinic antagonist. This enhanced binding was maximal with 20 mM K+ and was not due simply to a generalized ion effect, inasmuch as incubation of the cells with a concentration of Na+ of equivalent osmolarity did not alter alpha-BGT binding. Carbachol and the agonist nicotine completely prevented the K+-induced increase in the binding sites. In contrast to the marked up-regulation of the nicotinic alpha-BGT sites by K+, this agent did not increase the acetylcholine-induced release of [3H]noradrenaline from chromaffin cells in culture, further supporting the contention that the nicotinic alpha-BGT site and the functional nicotinic receptor are distinct. The increases in toxin binding due to K+ and d-tubocurarine were partially additive, suggesting that d-tubocurarine and K+ may share a common pathway, but only to a small degree. The calcium channel agonist BAY K 8644 and antagonist D600 had no effect on alpha-BGT binding either alone or in the presence of K+ or d-tubocurarine. On the other hand, forskolin, an activator of adenylate cyclase, and dibutyryl cAMP, an analog of cAMP, partially prevented the K+ and the d-tubocurarine-induced increases in toxin binding. These results suggest an involvement of cAMP in both the nicotinic antagonist-induced and K+-induced up-regulation of the sites. The observation that several mechanisms exist for the fine regulation of the nicotinic alpha-BGT binding sites in adrenal chromaffin cells could imply that this nicotinic receptor population plays a role in this tissue.
Mol Pharmacol 1988 Oct
PMID:Regulation of alpha-bungarotoxin sites in chromaffin cells in culture by nicotinic receptor ligands, K+, and cAMP. 245 93

The direct measurement of transmembrane calcium current in single vascular muscle cells has been accomplished recently using the whole-cell voltage-clamp technique. The small size of the vascular muscle cell and the proportionately smaller magnitude of its inward calcium current necessitate refined instrumentation, but also make the vascular muscle cell an ideal candidate for whole-cell voltage-clamp recording. Calcium current in vascular muscle cells appears to have some, but not all, characteristics in common with calcium currents similarly isolated in neuronal and cardiac cells, including voltage-dependent activation and steady-state inactivation of calcium current, the presence of two current types, and sensitivity to inorganic and organic calcium channel modulating drugs. Future voltage-clamp analysis of calcium currents in vascular muscle is needed to further our understanding of the control of the calcium channels in physiological and pathophysiological states.
Mol Cell Biochem
PMID:Measurement of whole-cell calcium current in voltage-clamped vascular muscle cells. 245 2

The modulation of L-type voltage sensitive calcium channels in isolated guinea pig ventricular myocytes by the dihydropyridine (+)-202-791 was examined with the whole-cell voltage-clamp technique with 1.8 mM Ba or Ca as the charge carrier. Striking voltage- and use-dependent effects of the dihydropyridine calcium channel "agonist" (+)-202-791 were revealed. From a holding potential of -60 mV, depolarizing test pulses in the presence of (+)-202-791 demonstrated a concentration-dependent (EC50, 177 nM) increase in the measured peak inward barium current compared to control. In contrast, more depolarized holding potentials (greater than or equal to -30 mV) (+)-202-791 caused a biphasic effect on the peak inward current resulting in a transient enhancement followed by a steady-state block. A saturable, concentration-dependent hyperpolarizing shift in the voltage dependence of current inactivation was observed in the presence of (+)-202-791 with an EC50 of 10.2 nM. The voltage dependence of current activation was also shifted in the hyperpolarizing direction in the presence of (+)-202-791. A use-dependent relative block by (+)-202-791 was observed after repetitive depolarizing test pulses at a frequency of 2 Hz. Thus, the single enantiomer (+)-202-791 can result in either an increase in the whole cell calcium channel current (favored by hyperpolarized holding potentials and low rates of stimulation) or block of calcium channel current (favored by depolarized holding potentials and high rates of stimulation). Various combinations of (-)-202-791, a reported calcium channel antagonist, and (+)-202-791 resulted in intermediate effects on voltage sensitive calcium or barium currents compared with the presence of either enantiomer alone, and no clear cooperative interactions between the enantiomers were observed in contrast to a previous single channel study (Kokuban S, Prod'ham B, Becker C, Porzig H, Reuter H: Studies on Ca channels in intact cardiac cells: Voltage-dependent effects and cooperative interaction of dihydropyridine enantiomers. Mol Pharmacol 1986;30:571-584). The results are discussed in relation to the possible presence of multiple dihydropyridine receptors associated with the voltage sensitive calcium channel.
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PMID:Voltage- and use-dependent modulation of cardiac calcium channels by the dihydropyridine (+)-202-791. 246 85

To define the cellular mechanism of action of a dihydropyridine Ca channel antagonist in an experimental model system devoid of neural influences and reflex effects, we studied the actions of RS93522 on cultured vascular smooth muscle cells and on cultured chick embryo ventricular cells. 45Ca uptake by monolayer cultures of vascular smooth muscle cells was inhibited in a concentration-dependent manner. The IC50 for this effect was 10 nM, similar to that for nifedipine (7 nM) in the same system. 10(-6) M RS93522 inhibited 45Ca uptake more fully than 10(-6) M nifedipine (P less than 0.05). Using an optical-video system, the effect of RS93522 on amplitude of contraction of spontaneously beating cultured ventricular cells was studied. Amplitude of contraction was inhibited with IC50 = 7.9 x 10(-8)M. 45Ca uptake in myocytes was depressed by 15% at 5 min. RS93522 had the additional property of inhibiting phosphodiesterase activity in myocardial homogenates with IC50 = 1.6 x 10(-5)M; the potency and efficacy of phosphodiesterase inhibition was similar to that for milrinone in the same system. As expected of Ca channel antagonists, it has a negative inotropic effect on cultured myocardial cells. The compound also has phosphodiesterase inhibitory activity that possibly may potentiate vasodilatation and ameliorate, in part, negative inotropic effects. Thus, RS93522 has two distinct pharmacodynamic effects in myocytes and is a potent calcium channel blocker.
J Mol Cell Cardiol 1988 Dec
PMID:A dihydropyridine calcium channel blocker with phosphodiesterase inhibitory activity: effects on cultured vascular smooth muscle and cultured heart cells. 247 Sep 9

Recent data have implicated the phosphatidylinositol/calcium second-messenger system in the control of aldosterone secretion by the adrenal zona glomerulosa. However, in the rat adrenal there are few reports of a direct effect of protein kinase C activation on steroid secretion, while the effects of calcium mobilization may be variable. Since the rat adrenal zona glomerulosa is sensitive to the mode of tissue preparation, these mechanisms were reinvestigated in intact (non-dispersed) capsular tissue and collagenase-dispersed zona glomerulosa cells. Steroidogenesis in the intact zona glomerulosa was markedly affected by agonists of the calcium messenger system. Most notably, aldosterone and 18-hydroxycorticosterone (18-OH-B) secretion were stimulated by A23187 (100 nmol to 10 mumols/l) and BAY K 8644 (500 nmol/l). Phorbol 12-myristate 13-acetate (TPA; 1 pmol to 1 mumol/l) stimulated aldosterone secretion at all doses and caused a dose-dependent increase in 18-OH-B and 18-hydroxydeoxycorticosterone (18-OH-DOC) secretion. Corticosterone secretion was slightly increased in the presence of A23187 but not by TPA or BAY K 8644. Production of 18-OH-DOC was unaffected by A23187 and BAY K 8644. The calcium channel antagonist verapamil (10 mumols/l) inhibited ACTH-stimulated aldosterone secretion by the intact zona glomerulosa but had no effect on corticosterone secretion. Verapamil (10 mumols/l) also inhibited the increase in aldosterone secretion by collagenase-dispersed zona glomerulosa cells stimulated by ACTH (100 fmol to 100 nmol/l), angiotensin II (100 pmol to 10 nmol/l) and potassium (5.9 and 8.4 mmol/l); stimulated corticosterone secretion was unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)
J Mol Endocrinol 1989 Mar
PMID:Specific effects of agonists of the calcium messenger system on secretion of 'late-pathway' steroid products by intact tissue and dispersed cells of the rat adrenal zona glomerulosa. 247 55

This paper presents a view of the evolution and phylogenetic distribution of ionic channels of biological membranes. The view is based on the assumptions that ionic channels (1) appeared very early in the history of life, (2) have evolved from a common ancestor, and (3) have been subjected to evolutionary pressure to reach precision and high speed of signaling. We propose that Ca2+ was the intracellular messenger and modulator of the most primitive biological systems, which implies that the first channel to appear may have been a calcium channel. Then, very soon the entire group of potassium channels evolved from the calcium channel to improve the shape of signals and to restore initial conditions. Sodium channels probably appeared relatively late, diversifying from calcium channels in the early metazoan groups. Mainly because Na+ ions do not interfere with cellular metabolism (thus allowing the inward current--and, consequently, the speed of conduction--to be greatly increased), sodium channels probably proved advantageous in the generation of the action potential, and selection replaced calcium channels with sodium channels in this function. Finally, with the acquisition of multicellularity, channels responsible for synaptic transmission appeared. The case of the acetylcholine receptor channel is briefly discussed.
Mol Biol Evol 1989 Sep
PMID:Evolution of ionic channels of biological membranes. 247 61

This report describes a series of studies on the regulation of teleocalcin secretion by primary cultures of rainbow trout corpuscles of Stannius, endocrine glands believed to be unique to bony fishes. Teleocalcin release by these cultured cells was stimulated specifically by calcium in a dose-related fashion. Magnesium did not mimic the effects of added calcium and varying the osmotic pressure had no effect on hormone release. The addition of either ethyleneglycol-bis-(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) or cobalt chloride blocked the stimulatory effects of added calcium, whereas the calcium ionophore A23187 mimicked the effects of calcium on hormone release. Mammalian and piscine pituitary hormones (prolactin, growth hormone and gonadotrophic hormone) had no effect on teleocalcin secretion. Inconclusive results were obtained with the calcium channel blockers, verapamil and nifedipine. The results are discussed in relation to calcium-regulated secretion of calcitonin and parathyroid hormone, as well as the known physiological effects of teleocalcin in fish.
Mol Cell Endocrinol 1989 Mar
PMID:Primary culture of teleocalcin cells from rainbow trout corpuscles of Stannius: regulation of teleocalcin secretion by calcium. 250 Nov 23

The diuresis associated with rapid atrial rhythms is a well recognized clinical entity (Wood, 1963). Atrial natriuretic peptide (ANP) levels are elevated during rapid atrial rhythms (Hirata et al., 1987), including during rapid atrial pacing (Rankin et al., 1986; Schiebinger and Linden 1986; Walsh et al., 1987), and may contribute to the associated diuresis. Calcium channel antagonists are often used to treat atrial tachycardias but the effect this may have on ANP secretion and subsequent compensatory responses, such as a diuresis, is unknown. Reported here are experiments demonstrating that the increase in ANP secretion that accompanies rapid atrial pacing of the isolated perfused rat heart is abolished by calcium channel antagonists. This effect is not limited to a single class of calcium channel antagonists and could be demonstrated with Verapamil and Nifedipine. Although extrapolation to the in vivo situation should always be done with care, the results reported here contribute towards clarifying the effect of the calcium channel antagonists on the ANP response to rapid heart rates.
J Mol Cell Cardiol 1989 May
PMID:The effect of calcium antagonists on atrial natriuretic peptide (ANP) release from the rat heart during rapid cardiac pacing. 252 39

SR33557 belongs to a new class of molecules (indolizinsulfones) that act on the same receptor complex that has been characterized for other classical calcium channel effectors. The main binding properties of SR33557 to rabbit skeletal muscle are as follows. (i) Unlabeled SR33557 completely inhibits the specific binding of all classes of calcium channel antagonists such as dihydropyridines [(+)-[3H]PN200-110], phenylalkylamines ([3H] verapamil), benzothiazepines (d-(cis)-[3H]diltiazem), and diphenybutylpiperidines ([3H]fluspirilene). In all these cases inhibition of binding is of a noncompetitive nature. (ii) [3H]SR33557 binds with high affinity to T tubule membranes (KD = 0.08 nM) and the maximum binding capacity (Bmax = 78 pmol/mg of protein) is the same as that found for other classes of Ca2+ channel antagonists. Photoaffinity labeling confirms that [3H]SR33557 associates with the same protein of Mr 165,000 that binds the classical calcium channel inhibitors. 45Ca2+ uptake experiments performed with the rat aortic cell line A7r5, the insulin-secreting cell line RINm5F, and the pheochromocytoma cell line PC12 demonstrate that SR33557 fully inhibits the 1,4-dihydropyridine-sensitive 45Ca2+ uptake elicited by depolarization. A very good correlation was found between inhibition of 45Ca2+ uptake and of [3H]dopamine release in PC12 cells and between inhibition of 45Ca2+ uptake and of L-type Ca2+ current in A7r5 cells under whole-cell patch-clamp conditions.
Mol Pharmacol 1989 Jun
PMID:SR33557, an indolizinsulfone blocker of Ca2+ channels: identification of receptor sites and analysis of its mode of action. 254 10

The binding of dihydropyridine calcium channel agonists and antagonists to receptors in cardiac sarcolemmal membranes is a complex reaction that may involve an interaction with the lipid bilayer matrix of the sarcolemma. Membrane/buffer partition coefficients (lambda) for three dihydropyridine calcium channel antagonists were measured directly in the sarcolemma and sarcoplasmic reticulum membranes and found to be in the range of 5,000 to 150,000. These drugs interact primarily with the membrane bilayer component of these membranes but may also bind to non-receptor proteins. The intrinsic forward rate constants for dihydropyridine binding to sarcolemmal calcium channel receptors were apparently not strongly dependent on their membrane partition coefficients. For example, nimodipine (lambda = 6300) had a forward rate constant of 6.8 +/- 0.6 x 10(6)/M/S, whereas the forward rate constant for Bay P 8857 (lambda = 149,000) was 1.4 +/- 0.8 x 10(7)/M/S. Model calculations for this binding reaction demonstrated that since these drugs are highly lipid soluble, the dependence of these rates on lipid solubility would probably not be reflected in the experimental forward rate constants. In addition, the intrinsic forward rate constant for nimodipine binding to sarcolemmal calcium channel receptors was found not to be linearly dependent on the viscosity of the buffer medium over a five-fold range. The rate of nonspecific (non-receptor protein) drug binding to highly purified sarcoplasmic reticulum membranes essentially devoid of specific receptors for these drugs appears to be extremely fast, at least 10(3) times faster than specific drug binding to the receptor in the sarcolemma. Thus, it appears that partitioning into the lipid bilayer matrix of the sarcolemma could be a general property of dihydropyridine calcium channel antagonists and may be a prerequisite for their binding to sarcolemmal membrane receptors.
J Mol Cell Cardiol 1989 Feb
PMID:Interaction of 1,4 dihydropyridine calcium channel antagonists with biological membranes: lipid bilayer partitioning could occur before drug binding to receptors. 254 86


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