The Shaker gene of the fruit fly encodes voltage-dependent K+ channel proteins. The long-term goals of the research are to derive a biochemical model for the structure of the channel, and to correlate its functional properties with its structure.
The specific aims are: 1) to study the function of the conserved S4 sequence, which has been proposed to be the voltage-sensor of the channel. Single amino acid mutations will be made in the S4 basic amino acids, acidic residues that might form ion pairs with the S4, and control residues. The mutant channels will be expressed in Xenopus oocytes and analyzed electrophysiologically. 2) to study the disposition of the Shaker proteins in the membrane. The modification of potential sites for posttranslational glycosylation will be studied in in vitro translation reactions and in vivo. If these sites are modified in vivo, their topological location can be inferred. 3) to study the subunit structure of the channel. The Shaker gene will be expressed in a tissue culture system to begin biochemical experiments with the eventual goals of purifying the channel and determining the number of Shaker subunits per channel. K+ channels in the nervous system are implicated in the basic mechanisms of epileptogenesis. K+ channels in smooth muscle are promising pharmacological targets for the control of hypertension and stroke. K+ channels in lymphocytes are altered in a mouse model for lupus erythematosus. Therefore, studying the structure and function of K+ channels will contribute to our understanding of the etiology and treatment of a variety of diseases.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Physiology Study Section (PHY)
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University of California Los Angeles
Schools of Medicine
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Lin, Meng-Chin A; Cannon, Stephen C; Papazian, Diane M (2018) Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening. Proc Natl Acad Sci U S A 115:E3559-E3568
Duarri, Anna; Lin, Meng-Chin A; Fokkens, Michiel R et al. (2015) Spinocerebellar ataxia type 19/22 mutations alter heterocomplex Kv4.3 channel function and gating in a dominant manner. Cell Mol Life Sci 72:3387-99
Lee, Hane; Lin, Meng-chin A; Kornblum, Harley I et al. (2014) Exome sequencing identifies de novo gain of function missense mutation in KCND2 in identical twins with autism and seizures that slows potassium channel inactivation. Hum Mol Genet 23:3481-9
Lin, Meng-chin A; Hsieh, Jui-Yi; Mock, Allan F et al. (2011) R1 in the Shaker S4 occupies the gating charge transfer center in the resting state. J Gen Physiol 138:155-63
Lin, Meng-chin A; Abramson, Jeff; Papazian, Diane M (2010) Transfer of ion binding site from ether-a-go-go to Shaker: Mg2+ binds to resting state to modulate channel opening. J Gen Physiol 135:415-31
Koag, Myong-Chul; Papazian, Diane M (2009) Voltage-dependent conformational changes of KVAP S4 segment in bacterial membrane environment. Channels (Austin) 3:356-65
Lin, Meng Chin A; Papazian, Diane M (2007) Differences between ion binding to eag and HERG voltage sensors contribute to differential regulation of activation and deactivation gating. Channels (Austin) 1:429-37
Waters, Michael F; Minassian, Natali A; Stevanin, Giovanni et al. (2006) Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes. Nat Genet 38:447-51
Bannister, John P A; Chanda, Baron; Bezanilla, Francisco et al. (2005) Optical detection of rate-determining ion-modulated conformational changes of the ether-a-go-go K+ channel voltage sensor. Proc Natl Acad Sci U S A 102:18718-23
Silverman, W R; Tang, C Y; Mock, A F et al. (2000) Mg(2+) modulates voltage-dependent activation in ether-a-go-go potassium channels by binding between transmembrane segments S2 and S3. J Gen Physiol 116:663-78

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