The long-term objectives are to understand how individual potassium (K+) channels regulate neuronal excitability, using a combination of physiological and molecular approaches starting with positional cloning of the first voltage-gated K+ channel (with six transmembrane segments per subunit) in 1987 and expression cloning of one of the first two inwardly rectifying K+ channels (with two TM segments per subunit) in 1993. It is now well known that the 6-TM Kv channels and 2-TM Kir channels constitute two very large families of structurally related K* channels. The health relatedness of the project is evident from the fact that K+ channels are linked to human diseases of the brain, ear, heart, muscle and other organs. Indeed, K+ channel blockers and openers have been developed for pharmaceutical purposes, for the treatment of epilepsies, stroke, migraine, arrhythmias, diabetes, hypertension, neuropathic pain, and anxiety-related disorders. Having used the simpler 2-TM Kir channels to develop new methodologies, such as the unbiased approach of relying on yeast screens of randomly mutagenized K+ channels to deduce how TM helices are arranged in a K+ channel-an approach validated by the excellent agreement between predictions made in 1999 based on yeast studies of mammalian Kir2.1 channels and the bacterial KirBad.1 structure reported in 2003, we plan to apply these new methods to study how the 6 TM helices are arranged in a Kv channel. With a long-standing interest in the question how neurons control the number and location of their K+ channels, thereby allowing these channels to fulfill their physiological functions, we will make use of the conceptual and technological advances made in recent studies of channel trafficking and targeting, and pursue the following questions: (1) How might the Kv1 channel protein level be regulated in cultured hippocampal neurons and cortical neurons? Preliminary studies using a translation reporter we developed have identified one signaling pathway for this regulation. (2) What mediates the axonal targeting of Kv1 channels? We will pursue new leads obtained with the assays we have worked out to quantify the relative abundance of K+ channels on the surface of axons versus dendrites of cultured hippocampal neurons. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37MH065334-26
Application #
7038711
Study Section
Biophysics of Synapses, Channels, and Transporters Study Section (BSCT)
Program Officer
Asanuma, Chiiko
Project Start
2001-09-01
Project End
2011-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
26
Fiscal Year
2006
Total Cost
$383,750
Indirect Cost
Name
University of California San Francisco
Department
Physiology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Yadav, Smita; Oses-Prieto, Juan A; Peters, Christian J et al. (2017) TAOK2 Kinase Mediates PSD95 Stability and Dendritic Spine Maturation through Septin7 Phosphorylation. Neuron 93:379-393
Thayer, Desiree A; Yang, Shi-Bing; Jan, Yuh Nung et al. (2016) N-linked glycosylation of Kv1.2 voltage-gated potassium channel facilitates cell surface expression and enhances the stability of internalized channels. J Physiol 594:6701-6713
Huang, Xi; He, Ye; Dubuc, Adrian M et al. (2015) EAG2 potassium channel with evolutionarily conserved function as a brain tumor target. Nat Neurosci 18:1236-46
Huang, Xi; Jan, Lily Yeh (2014) Targeting potassium channels in cancer. J Cell Biol 206:151-62
Hong, TingTing; Yang, Huanghe; Zhang, Shan-Shan et al. (2014) Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia. Nat Med 20:624-32
Huang, Fen; Wang, Xidao; Ostertag, Eric M et al. (2013) TMEM16C facilitates Na(+)-activated K+ currents in rat sensory neurons and regulates pain processing. Nat Neurosci 16:1284-90
Isacoff, Ehud Y; Jan, Lily Y; Minor Jr, Daniel L (2013) Conduits of life's spark: a perspective on ion channel research since the birth of neuron. Neuron 80:658-74
Sun, Yaping; Dong, Zhiqiang; Jin, Taihao et al. (2013) Imaging-based chemical screening reveals activity-dependent neural differentiation of pluripotent stem cells. Elife 2:e00508
Thayer, Desiree A; Jan, Yuh Nung; Jan, Lily Yeh (2013) Increased neuronal activity fragments the Golgi complex. Proc Natl Acad Sci U S A 110:1482-7
Yang, Huanghe; Kim, Andrew; David, Tovo et al. (2012) TMEM16F forms a Ca2+-activated cation channel required for lipid scrambling in platelets during blood coagulation. Cell 151:111-22

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