Electrical excitability is primarily mediated by ion channel proteins which selectively conduct different ions. Regulation of ion channels by enzymes is central to confer their biological diversity and respond to physiological changes. The ability to sense both electrical signals and chemical signals endows an ion channel critical roles in diverse biological systems. The large conductance calcium-activated (BK) potassium channels are gated both by membrane potential voltage and by cytoplasmic calcium concentration. Because action potential is central to membrane excitability and the intracellular calcium concentration is coupled with a wide variety of biological processes, the functional roles of BK channels are accordingly diverse and of great significance. One important mechanism of coding functional diversity is through alternative splicing of pore-forming subunit, known as alpha subunit. The current understanding of BK structure and function is, almost exclusively, based on studies of one type of C-terminal splice variants known as BK_ERL. The direct evidence linking native BK channel properties and the corresponding molecular isoforms of BK subunits is not yet adequate to fully establish that the ERL isoform is the most important form for the in vivo function. Another C-terminal splice variant, BK_DEC, has additional 61 aa distinct from commonly studied ERL form. We now show this region is densely packed with functional motifs and represents an enzymatic assembly domain recruiting a number of enzymes and regulatory factors. This research proposal is aimed at investigating newly identified enzymatic complexes organized by BKJDEC.
The specific aims i nclude biochemical, cell biological and functional characterization of these newly identified protein complexes. BK channels are critical for a variety of biological processes ranging from hormone secretion to control of neuronal firing properties. Drugs have been developed to regulate these channels'activity to treat human diseases such as stroke, epilepsy and other neurological disorders. Thus, understanding of the function and physiology of different BK subtypes is of therapeutics importance.
Showing the most recent 10 out of 27 publications
