Effects of familial hemiplegic migraine type 1 mutations on neuronal P/Q-type Ca2+ channel activity and inhibitory synaptic transmission.
Inhibitory synapses play key roles in the modulatory circuitry that regulates pain signaling and generation of migraine headache. A rare, dominant form of this common disease, familial hemiplegic migraine type 1 (FHM1), arises from missense mutations in the pore-forming alpha1A subunit of P/Q-type Ca2+ channels. These channels are normally vital for presynaptic Ca2+ entry and neurotransmitter release at many central synapses, raising questions about effects of FHM1 mutations on neuronal Ca2+ influx and inhibitory and excitatory neurotransmission. We have expressed the four original FHM1 mutant channels in hippocampal neurons from alpha1A knockout mice. Whole-cell recordings indicated that FHM1 mutant channels were less effective than wild-type channels in their ability to conduct P/Q-type current, but not generally different from wild type in voltage-dependent channel gating. Ca2+ influx triggered by action potential waveforms was also diminished. In keeping with decreased channel activity, FHM1 mutant channels were correspondingly impaired in supporting the P/Q-type component of inhibitory neurotransmission. When expressed in wild-type inhibitory neurons, FHM1 mutant channels reduced the contribution of P/Q-type channels to GABAergic synaptic currents, consistent with a competition of mutant and endogenous channels for P/Q-specific slots. In all cases, N-type channels took up the burden of supporting transmission and homeostatic mechanisms maintained overall synaptic strength. The shift to reliance on N-type channels greatly increased the susceptibility to G protein-coupled modulation of neurotransmission, studied with the GABAB agonist baclofen. Thus, mutant-expressing synapses might be weakened in a heightened state of neuromodulation like that provoked by triggers of migraine such as stress.
Cao
Yu-Qing
YQ
Department of Molecular and Cellular Physiology, Beckman Center, Stanford University School of Medicine, Stanford, CA 94305-5345, USA.
Tsien
Richard W
RW
D000818:Animals; D020865:Calcium Channels, P-Type / Q000235:genetics* / Q000378:metabolism*; D020907:Calcium Channels, Q-Type / Q000235:genetics* / Q000378:metabolism*; D020013:Calcium Signaling; D015870:Gene Expression; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008881:Migraine Disorders / Q000145:classification / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics; D014162:Transfection
D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D018080:Receptors, GABA-B