Presynaptic Ca²⁺ channels compete for channel type-preferring slots in altered neurotransmission arising from Ca²⁺ channelopathy

Several human channelopathies result from mutations in α _1A, the pore-forming subunit of P/Q-type Ca²⁺ channels, conduits of presynaptic Ca²⁺ entry for evoked neurotransmission. We found that wild-type human α_1A subunits supported transmission between cultured mouse hippocampal neurons equally well as endogenous mouse α_1A, whereas introduction of impermeant human α_1A 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 α_1A 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.