Gating of Neuronal Kv4 Channels

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The long~term goal of this project is to shed light on t molecular mechanisms that govern the function and regulation of the neuronal somatodendritic A~type assium current (I$A), Typically, ISA operates in the subthreshold range of membrane potentials and is a pivotal player in the ensemble of active membrane currents that regulate somatodendrilic signal integrati9n;therefore, it has a broad impact on the electrical plasticity of the brain. The Kv4 channel complex is th~ l moleculpr correlate of ISA. This complex includes the KV4 pore-forming a.~subunit encompassing three modulrr domains common to all voltage-gated K" channets: tetramerization (T1) domain, voltage-sensing domain a~ pore domain. In addition, Kv4 ((~subunits associate with at least two specific classes of auxiliary p~subunits ChiPs and DPPs). Although ground breaking S1udies of the OfO$ophila Shaker~B and bacterial potassium annels have helped explain fundamental properties (ionic selectivity, voltage-dependent gating and open-s te inactivation), many problems conceming relevant regulatory mechanisms remain unsolved. Given th cytoplasmic location of the T1 domain, its likely contribution to gating is one of the most intriguing Probl~ms . With NINDS suppon, previous studies from the PI's laboratory strongly support this contribution in Kv channels and its modulation by nitric oxide (NO). However, the molecular mechanisms have remained elu ive. To break new ground, this project will investigate the molecular mechanisms under1ying the contributions of the T1 domain to activation (Aim 1) and inactivation (Aim 2) in the Kv4 channel complex. The proposed actIvity will focus on putative moving parts that surround the interfacial Zn .... site, which is the targ~ of NO mod y l~lon;. and t~e exp~rimental approach is based ?n a multidiscIplinary research plan that combines electrop~StOloglcal , biochemical, molecular and computational methOdologies. This work is likely to impact the stud of neurological entities possibly linked to the Kv4 channel complex, such as epilepsy, pain plasticity, neur egenerative disorders, and autism.
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