A functional correlate for the dihydropyridine binding site in rat brain

Abstract

Calcium channels, controlling the influx of extracellular Ca²⁺ and hence neurotransmitter release, exist in the brain¹. However, drugs classed as calcium antagonists and which inhibit Ca²⁺ entry through voltage-activated Ca²⁺ channels in heart and smooth muscle², seem not to affect any aspect of neuronal function in the brain at pharmacologically relevant concentrations^3–6. Yet the dihydropyridine calcium antagonists (for example, nitrendipine) bind stereospecifically with high affinity to a recognition site on brain-cell membranes thought to represent the Ca²⁺ channel^4,7,8 and consequently, the physiological relevance of these sites has been questioned⁹. However, activation of voltage-dependent Ca²⁺ channels can increase cytoplasmic Ca²⁺ and neurotransmitter release in neuronal tissue¹⁰. We show here that Bay K 8644, a dihydrophyridine Ca²⁺-channel activator^11,12, can augment K⁺-stimulated release of serotonin from rat frontal cortex slices and that these effects can be antagonized by low concentrations of calcium antagonists. As ³H-dihydropyridine binding to cortical membrane preparations resembles the binding in heart and smooth muscle where there are good functional correlates^8,13 we conclude that the dihydropyridine binding sites in the brain represent functional Ca²⁺ channels that can be unmasked under certain circumstances.