NMDA receptor agonists selectively block N-type calcium channels in hippocampal neurons

Abstract

THEmodulation of voltage-dependent calcium channels by various neurotransmitters has been demonstrated in many neurons^1–4. Because of the critical role of Ca²⁺ in transmitter release and, more generally, in transmembrane signalling, this modulation has important functional implications. Hippocampal neurons possess low-threshold (T-type) Ca²⁺ channels and both L- and N-type high voltage-activated Ca²⁺ channels.^5–7N-type Ca²⁺ channels are blocked selectively by ω-conotoxin ^8,9 and adenosine ^10,11. These substances both block excitatory synaptic transmission in the hippocampus^12–13, whereas dihydropyridines, which selectively block L-type channels¹⁴, are ineffective¹². Excitatory synaptic transmission in the hippocampus displays a number of plasticity phenomena that are initiated by Ca²⁺ entry through ionic channels operated by N-methyl-D-aspartate (NMDA) receptors^15,16. Here we report that NMDA receptor agonists selectively and effectively depress N-type Ca²⁺ channels which are involved in neurotransmit-ter release from presynaptic sites. The inhibitory effect is eliminated by the competitive NMDA antagonist D-2-amino-5-phosphonovalerate, does not require Ca²⁺ entry into the cell, and is probably receptor-mediated. This phenomenon may provide a negative feedback between the liberation of excitatory transmitter and entry of Ca²⁺ into the cell, and could be important in presynaptic inhibition and in the regulation of synaptic plasticity.