Abstract 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 diseasecausing 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 4.5-fold the sensitivity of the channel to extracellular Zn++. Both Zn++ and Cd++ 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 Zn++ is likely to contribute to the EA1 symptoms in patients harboring the F184C mutation.
An Episodic Ataxia Type-1 (EA1) mutation in the S1 segment sensitises the hKv1.1 potassium channel to extracellular Zn2+
D'ADAMO M.C.;
2004-01-01
Abstract
Abstract 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 diseasecausing 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 4.5-fold the sensitivity of the channel to extracellular Zn++. Both Zn++ and Cd++ 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 Zn++ is likely to contribute to the EA1 symptoms in patients harboring the F184C mutation.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
