Presynaptic Ca2+ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca2+ channelopathy.
Several human channelopathies result from mutations in alpha1A, the pore-forming subunit of P/Q-type Ca2+ channels, conduits of presynaptic Ca2+ entry for evoked neurotransmission. We found that wild-type human alpha1A subunits supported transmission between cultured mouse hippocampal neurons equally well as endogenous mouse alpha1A, whereas introduction of impermeant human alpha1A hampered the effect of endogenous subunits. Thus, presynaptic P/Q-type channels may compete for channel type-preferring "slots" that limit their synaptic effectiveness. The existence of slots generates predictions for how neurotransmission might be affected by changes in Ca2+ channel properties, which we tested by studying alpha1A mutations that are associated with familial hemiplegic migraine type 1 (FHM1). Mutant human P/Q-type channels were impaired in contributing to neurotransmission in precise accord with their deficiency in supporting whole-cell Ca2+ channel activity. Expression of mutant channels in wild-type neurons reduced the synaptic contribution of P/Q-type channels, suggesting that competition for type-preferring slots might support the dominant inheritance of FHM1.
Cao
Yu-Qing
YQ
Department of Molecular and Cellular Physiology, Beckman Center, Stanford University School of Medicine, Stanford, CA 94305, USA.
Piedras-Rentería
Erika S
ES
Smith
Geoffrey B
GB
Chen
Gong
G
Harata
Nobutoshi C
NC
Tsien
Richard W
RW
D000818:Animals; D015220:Calcium Channels / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology*; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D002460:Cell Line; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D020325:Migraine with Aura / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D017729:Presynaptic Terminals / Q000502:physiology*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*
D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; C105656:CACNA1A protein, human