Properties of Inward Rectifier K Channels

University Of California Los Angeles, Los Angeles CA

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Abstract

Inward rectifier K (Kir) channels are essential for the normal function[unreadable] of both excitable and nonexcitable cells. The specific aims of this[unreadable] proposal are two-fold: to better understand the mechanisms of inward[unreadable] strong rectification in Kir2.1 (IRK1), the major component of the high[unreadable] resting K conductance in many cell types, and to investigate the basis[unreadable] of mechanosensitivity of the G-protein regulated K channel Kir3.4[unreadable] (GIRK4), a major component of the resting K conductance in atrial muscle[unreadable] and brain. We will apply electrophysiological (patch-clamp), molecular[unreadable] biological and biochemical techniques to various cloned Kir channels[unreadable] expressed in Xenopus oocytes or mammalian cell lines. In the first[unreadable] specific aim, we will determine how an intrinsic gating mechanism, which[unreadable] we have recently identified and postulate to be a tethered gating[unreadable] particle, interacts with polyamines and Mg to contribute to strong[unreadable] inward reactivation in Kir channels. We will test the novel hypothesis[unreadable] that the tethered gating particle contains binding sites for polyamines[unreadable] and Mg which enhances its ability to cause inward rectification,[unreadable] providing further insight into the molecular basis of strong inward[unreadable] rectification. In the second specific aim, we will characterize the[unreadable] molecular mechanisms underlying stretch-induced inactivation of Kir3.x[unreadable] channels, a property which we have recently identified in Kir3.4 and[unreadable] native cardiac KACh channels. We will determine: whether[unreadable] mechanosensitivity is also a property of other members of the Kir3.x[unreadable] family, the regions of the Kir3.4 channel required for[unreadable] mechanosensitivity, using chimeric constructs and site-directed[unreadable] mutagenesis; the role of G proteins; and the cytoskeletal and/or[unreadable] extracellular matrix elements responsible for transducing[unreadable] mechanosensitivity. The mechanosensitivity of Kir3.x channels may[unreadable] contribute to a variety of stretch-induced responses, including stretch-[unreadable] induced arrhythmias, atrial natriuretic peptide (ANP) release, and/or[unreadable] hypertrophic gene programming. Together, these studies in Kir channels[unreadable] will provide important insights into the regulation of excitability in[unreadable] ventricular and atrial cardiac muscle, as well as in other excitable[unreadable] tissues.