Properties of human Cav2.1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells.
Spinocerebellar ataxia type 6 (SCA6) is caused by polyglutamine expansion in P/Q-type Ca2+ channels (Ca(v)2.1) and is characterized by predominant degeneration of cerebellar Purkinje cells. To characterize the Ca(v)2.1 channel with an SCA6 mutation in cerebellar Purkinje cells, we have generated knock-in mouse models that express human Ca(v)2.1 with 28 polyglutamine repeats (disease range) and with 13 polyglutamine repeats (normal range). Patch-clamp recordings of the Purkinje cells from homozygous control or SCA6 knock-in mice revealed a non-inactivating current that is highly sensitive to a spider toxin omega-Agatoxin IVA, indicating that the human Ca(v)2.1 expressed in Purkinje cells exhibits typical P-type properties in contrast to the previous data showing Q-type properties, when it was expressed in cultured cell lines. Furthermore, the voltage dependence of activation and inactivation and current density were not different between SCA6 and control, though these properties were altered in previous reports using non-neuronal cells as expression systems. Therefore, our results do not support the notion that the alteration of the channel properties may underlie the pathogenic mechanism of SCA6.
Saegusa
Hironao
H
Department of Pharmacology and Neurobiology, Graduate School of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Tokyo 113-8519, Japan.
Wakamori
Minoru
M
Matsuda
Yoshihiro
Y
Wang
Junyang
J
Mori
Yasuo
Y
Zong
Shuqin
S
Tanabe
Tsutomu
T
D000367:Age Factors; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004558:Electric Stimulation / Q000379:methods; D005786:Gene Expression Regulation / Q000502:physiology / Q000528:radiation effects*; D006801:Humans; D017403:In Situ Hybridization; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D010455:Peptides / Q000235:genetics; D011689:Purkinje Cells; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020867:omega-Agatoxin IVA / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D010455:Peptides; D020867:omega-Agatoxin IVA; C105656:CACNA1A protein, human; C097188:polyglutamine