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 concentration of extracellular Ca2+ (Ca[2+]o) (CaR) is functionally coupled to ion channels involved in modulation of neuronal excitability. This receptor is expressed in hippocampus and other brain regions, suggesting that it could mediate some of the well-recognized but poorly understood direct actions of extracellular Ca2+ (Ca[2+]o) on neuronal function. The effects of polycationic CaR agonists on the activity of a nonselective cation channel (NCC) in cultured hippocampal neurons from wild-type mice and from mice homozygous for targeted disruption of the CaR gene (CaR -/-) were compared in this study. The CaR agonists, neomycin (100 microM), spermine (300 microM), and elevation of Ca(2+)o from 0.75 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, however, could be activated by thapsigargin in neurons from both wild-type mice and CaR-deficient mice, most likely through an associated increase in the cytosolic free calcium concentration (Ca[i]). Thus the CaR regulates the activity of Ca2+-permeable NCC in hippocampal neurons and could potentially modulate key neuronal functions, including neurotransmission and neuronal excitability, via membrane depolarization.
Ye
C
C
Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.
Ho-Pao
C L
CL
Kanazirska
M
M
Quinn
S
S
Seidman
C E
CE
Seidman
J G
JG
Brown
E M
EM
Vassilev
P M
PM
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002412:Cations / Q000378:metabolism*; D005796:Genes / Q000235:genetics*; D006624:Hippocampus / Q000502:physiology*; D007473:Ion Channels / Q000172:deficiency*; D051379:Mice; D008817:Mice, Mutant Strains; D009355:Neomycin / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D013096:Spermine / Q000494:pharmacology
D002412:Cations; D007473:Ion Channels; D011500:Protein Synthesis Inhibitors; D013096:Spermine; D009355:Neomycin; D002118:Calcium