Modulation of Ca channels in peripheral neurons

Modulation of voltage-dependent Ca channels is of great significance for the control of Ca-dependent neuronal activities. Neuronal Ca channels can be modulated in many ways but, very likely, only a few common mechanisms underly these actions. An external receptor site is generally thought to be coupled to the functional parts of Ca channels through cyclic-nucleotide-mediated mechanisms. Occupancy of the receptor site by an agonist induces a cascade of reactions that lead either to activation, inhibition or modifications of the open-closed kinetics of the pore. Recent studies begin to reveal some details of the receptor-Ca channel. Alternatively, Ca-channel modulation by external ligands has proved to be useful for investigating the side groups controlling channel gatings and ion permeability. In this paper we will review three types of modulatory effects that apparently escape the “canonical schemes” of Ca-channel modulation. Two of them (dopamine and menthol) relate to specific modifications of the activation and inactivation gates of high-threshold (HVA; L, N) Ca channels. In peripheral neurons, dopamine drastically slows the activation kinetics of HVA Ca channels, while menthol speeds up their time-dependent inactivation. The third modulatory effect concerns the ability of permeant ions (Ca2+ or Na+) to influence the binding of the neurotoxic peptide w-conotoxin (o-CgTX) to high-threshold Ca channels? w-CgTX blocks the channels slowly and persistently when Ca2+ is the main current-carrying but blocks them quickly and reversibly when Na+ crosses the pore, as if the toxin were able to distinguish Ca- from Na-permeable states of the same channel.