RNA editing of the human K(v)1.1 potassium channel.

摘要

Potassium (K+) channels in the nervous system serve many roles: maintaining the resting membrane potential, regulating cell volume, and tuning the firing properties of a given neuron. The delayed rectifier function of K+ channels allows nerve cells to efficiently repolarize following an action potential. Mutations in K+ channels have been reported to cause many neurological diseases. Episodic Ataxia/Myokymia Syndrome Type 1 (EA1) is the only human ataxia known to be caused by dysfunction of a K+ channel EA1 is an inherited autosomal dominant human neurological disorder that affects both peripheral and central nerve functions. In addition, patients affected by EA1 have an estimated 10-fold increased risk to develop epilepsy. The gene responsible for EA1 has been identified as KCNA1, which encodes the Shaker-like voltage gated potassium channel Kv1.1 in mammals. Most mutations that underlie EA1 have been shown to alter the biophysical properties of Kv1.1 channels.; Adenosine-to-inosine (A-to-I) pre-mRNA editing is a post-transcriptional chemical modification, which generates an RNA transcript with a nucleotide sequence different from its gene. We have discovered that the KCNA1 transcript is a target of RNA editing in its coding sequence at a very highly conserved amino-acid position. We have also observed that the spatial regulation of RNA editing for Kv1.1 is evolutionarily conserved between rodents and humans. RNA editing at this site causes an isoleucine to valine change at a residue position known to be important for channel function. The studies below aim to understand the functional consequences of RNA editing of Kv1.1 in the mammalian nervous system.