Regulation of neuronal and skeletal muscle potassium channels
We study a family of five single transmembrane domain potassium channel ancillary subunits called the MinK-related peptides (MiRPs, encoded by KCNE genes). MiRPs co-assemble with pore-forming potassium channel alpha subunits, forming heteromeric complexes with functional features distinct from their homomeric counterparts.
Historically, most of the research into the MiRP family has focused on the heart, mainly because the founding member, MinK (KCNE1), helps to generate an important human cardiac potassium current (IKs).
More recently, the role of MiRPs in voltage-independent potassium channel complexes in mammalian polarized epithelial cells has been studied. Moving forward, one important area of MiRP biology that has been relatively overlooked is the role of MiRPs in regulating voltage-gated potassium (Kv) channels in the mammalian brain. Because of the criticality of exquisiste control of action potential morphology and duration to correct neruonal firing, one might expect that neuronally expressed MiRPs contribute to normal function of the central nervous system.
Skeletal muscle also requires Kv currents for the electrical activity underlying normal muscular contraction. To understand the molecular basis for skeletal muscle Kv currents, we need to identify all the subunits that constitute Kv channels in this tissue.
As with our studies of cardiac and epithelial potassium channels, we employ a combination of human genetics, transgenic mouse models, electrophysiology, protein chemistry, microscopy and molecular biology to discover novel roles for MiRPs and their Kv channel alpha subunit partners in neuronal and skeletal muscle physiology and disease.
Relevant articles
Choi E, Abbott GW. The MiRP2-Kv3.4 potassium channel: muscling in on Alzheimer's disease. Mol Pharmacol. 2007 Sep;72(3):499-501. Epub 2007 Jun 26. PMID: 17595326
Abbott G.W., Butler, M.H., & Goldstein, S.A. Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2-Kv3.4 potassium channels in periodic paralysis. FASEB Journal 20(2):293-301, 2006
Lewis A, McCrossan ZA, Abbott G.W. MinK, MiRP1, and MiRP2 diversify Kv3.1 and Kv3.2 potassium channel gating. J Biol Chem. 279(9):7884-92, 2004.
McCrossan ZA, Lewis A, Panaghie G, Jordan PN, Christini DJ, Lerner DJ, Abbott G.W. MinK-related peptide 2 modulates Kv2.1 and Kv3.1 potassium channels in mammalian brain. Journal of Neuroscience. 23(22):8077-91, 2003.
Abbott G.W., Butler, M.H., Bendahhou, S., Dalakas, M.C., Ptacek, L.J., & Goldstein, S.A.N. MiRP2 forms potassium channels in skeletal muscle with Kv3.4 and is associated with periodic paralysis. Cell 104:217-231, 2001.
