An episodic ataxia type-1 mutation in the S1 segment sensitises the hKv1.1 potassium channel to extracellular Zn2+.
Episodic ataxia type-1 (EA1) is a human neurological syndrome characterized by attacks of generalized ataxia and by continuous myokymia that has been associated with point mutations in the voltage-gated potassium channel gene KCNA1. Although important advancement has been made in understanding the molecular pathophysiology of EA1, several disease-causing mechanisms remain poorly understood. F184C is an EA1 mutation that is located within the S1 segment of the human Kv1.1 subunit. Here, we show that the F184C mutation increases approximately 4.5-fold the sensitivity of the channel to extracellular Zn2+. Both Zn2+and Cd2+ markedly alter the activation kinetics of F184C channel. In addition, the mutated channel reacts with several methane thiosulfonate reagents which specifically affected channel function. The results provide structural implications and indicate that sensitisation of hKv1.1 to Zn2+ is likely to contribute to the EA1 symptoms in patients harboring the F184C mutation.
Istituto di Ricerche Farmacologiche 'Mario Negri', CMNS, Santa Maria Imbaro (Chieti), Italy.
Antonella
A
Cusimano
Maria
M
Cristina D'Adamo
Mauro
M
Pessia
D000818:Animals; D002104:Cadmium / Q000494:pharmacology; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D015640:Ion Channel Gating; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections; D009865:Oocytes; D018408:Patch-Clamp Techniques; D017354:Point Mutation; D015221:Potassium Channels / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D012680:Sensitivity and Specificity; D014982:Xenopus laevis; D015032:Zinc / Q000494:pharmacology*
D015221:Potassium Channels; D012333:RNA, Messenger; D002104:Cadmium; D015032:Zinc