DEFICIENT CATION CHANNEL REGULATION IN NEURONS FROM MICE WITH TARGETED DISRUPTION OF THE EXTRACELLULAR CA2-SENSING RECEPTOR GENE()

This study presents evidence that a receptor sensitive to the concentr ation of extracellular Ca2+ (Ca-o(2+)) (CaR) is functionally coupled t o ion channels involved in modulation of neuronal excitability. This r eceptor is expressed in hippocampus and other brain regions, suggestin g that it could mediate some of the well-recognized but poorly underst ood direct actions of extracellular Ca2+ (Ca-o(2+)) on neuronal functi on. The effects of polycationic CaR agonists on the activity of a nons elective cation channel (NCC) in cultured hippocampal neurons from wil d-type mice and from mice homozygous for targeted disruption of the Ca R gene (CaR -/-) were compared in this study. The CaR agonists, neomyc in (100 mu M), spermine (300 mu M), and elevation of Ca-o(2+) from 0.7 5 to 3 mM, significantly increased the probability of channel opening (Po) in wild-type neurons. None of these agents, however, produced any effect on Po in neurons from mice lacking the CaR. The same NCC, howe ver, could be activated by thapsigargin in neurons from both wild-type mice and CaR-deficient mice, most likely through an associated increa se in the cytosolic free calcium concentration (Ca-i). Thus the CaR re gulates the activity of Ca2+-permeable NCC in hippocampal neurons and could potentially modulate key neuronal functions, including neurotran smission and neuronal excitability, via membrane depolarization. (C) 1 997 Elsevier Science Inc.