Multiple calcium channels mediate neurotransmitter release from peripheral neurons.

Abstract

We examined the effects of dihydropyridine drugs on evoked neurotransmitter release from cultured neonatal rat sensory and sympathetic neurons. Depolarization with K+-rich solutions increased the release of substance P from cultured sensory neurons. This release was enhanced by BAY K8644 and (+)-202791 and was blocked by a variety of other dihydropyridines including (-)-202791, by Co2+, or in Ca2+-free solutions. K+-rich solutions also stimulated the release of [3Hjnorepinephrine from cultured sympathetic neurons. This release was also completely blocked by Co2+ or in Ca2+-free solution. In contrast to the situation in sensory neurons, however, the evoked release of [3H]norepinephrine was completely resistant to the blocking effects of dihydropyridine such as nimodipine. However, BAY K8644 was able to enhance the evoked release of [3lHlnorepinephrine, and this enhancement was blocked by nimodipine. These results are discussed in relation to the possible participation of multiple types of calcium channels in the release of neurotransmitters.Experimental evidence from various sources has indicated that neurons and other excitable cells may possess several types of voltage-sensitive calcium channels (VSCC) (1)(2)(3)(4). These channels can be distinguished by their biophysical characteristics and also by their sensitivity to drugs, hormones, and toxins (reviewed in ref. 4). One type of VSCC has been characterized in several different tissues by its sensitivity to dihydropyridine drugs (2,(4)(5)(6)(7)(8). A subject of great current interest is the elucidation of the physiological functions of both dihydropyridine-sensitive and dihydropyridineinsensitive VSCC. In neurons, a major function of VSCC is to provide Ca2+ for triggering the release of neurotransmitters (stimulus-secretion coupling). The evoked release of neurotransmitters from neurons has generally proved to be insensitive to dihydropyridines (4, 9). Although transmitter release in general is dihydropyridine-insensitive, high-affinity dihydropyridine binding has been demonstrated on both central and peripheral nerves (reviewed in refs. 4 and 9). Such observations have produced some confusion, and clearly the functions of dihydropyridine-sensitive VSCC in neurons remain to be elucidated. In the present communication, we demonstrate that the release of the neurotransmitter substance P from sensory neurons is extremely dihydropyridinesensitive, whereas the release of norepinephrine from sympathetic neurons taken from the same animals is generally resistant to these drugs. These results indicate that both dihydropyridine-sensitive and dihydropyridine-insensitive VSCC may mediate stimulus-secretion coupling in different types of neurons. MATERIALS AND METHODSDihydropyridines and Other Drugs. Nitrendipine, nimodipine, and BAY K8644 were gifts of A. Scriabine (Miles Laboratories, West Haven, CT). Methoxyverapamil (D600) was a gift of Knoll Pharmaceuticals (Ludwigshafen, F.R.G.). The isomers of 202791 were gifts of Sandoz.[3H]Norepinephrine was purchased fro...

N-Type Calcium Channels Control Sympathetic Neurotransmission in Human Heart Atrium

“…High-affinity binding of dihydropyridines to nervous tissue has been demonstrated, and it has been proposed that these binding sites are L-type calcium channels. 19 However, in functional studies in which an inhibition of evoked norepinephrine release was observed by dihydropyridines and verapamil, it only occurred either at high stimulation frequencies (Ն10 Hz) or at drug concentrations Ն1 mol/L. 19 -23 In the present study, even 1 mol/L verapamil failed to inhibit evoked norepinephrine release at stimulation frequencies of up to 10 Hz.…”

Characterization of a calcium current in a vertebrate cholinergic presynaptic nerve terminal

“…They are, however, consistent with previous studies on presynaptic nerve terminal Ca channels at many fast-transmitting synapses using more indirect techniques. These include insensitivity to DHP blockers (see Nachsen and Blaustein, 1979;Pemey et al, 1986;Miller, 1987;Himing et al, 1988;Suszkiw et al, 1989), slow inactivation (Suszkiw et al, 1986), and sensitivity to w-CTX (Kerr and Yoshikami, 1984;Yoshikami et al, 1989).…”

Enhancement of voltage-gated Ca2+ currents induced by daily stimulation of hippocampal neurons with glutamate

“…It was initially proposed that either w-conotoxin (Miller, 1987) or dihydropyridine-sensitive HVA Zc, (Pemey et al, 1986;Rane et al, 1987) could mediate synaptic transmission. However, Regan et al (1991) have recently shown that in hippocampal cells, as in other mammalian neurons, much of the HVA IC, is resistent to both w-conotoxin and dihydropyridine blockers.…”