Cooper, M.D., Ph.D.
Cooper, M.D., Ph.D.
- Associate Professor
Neurology, Neuroscience, and Molecular & Human Genetics
Baylor College of Medicine
- Graduate Program Faculty
Translational Biology & Molecular Medicine;
Brain Disorders and Development
Baylor College of Medicine
- PhD from Yale University
- 01/1991 - New Haven, Connecticut United States
- Cellular and Molecular Physiology
- MD from Yale University
- 05/1990 - New Haven, Connecticut United States
- Residency at University Of California, San Francisco
- 06/1994 - San Francisco, California United States
- Post-Doctoral Fellowship at University of California
- 01/2002 - San Francisco, California United States
- Voltage-gated sodium and potassium channel diseases of the axon: evolution, mechanisms, animal models, and therapeutics
- Epilepsy and seizures
- Family history of epilepsy
Professional StatementThe major focus of our work is forms of human epilepsy arising from mutations in voltage-gated sodium and potassium channels. We discovered that KCNQ potassium channels were concentrated in the axon, and identified the first molecular mechanisms for KCNQ channel targeting at the axonal initial segment and nodes of Ranvier. We have contributed to the first physiological demonstrations of KCNQ2 channel function in identified PNS and CNS axons. We have used molecular phylogenetics and comparative anatomy to identify previously unknown functional domains of KCNQ channels and interacting proteins. Using such approaches, we showed that the targeting of certain KCNQ channels to axons is an outcome of convergent evolution in early vertebrates. In an unusual example of molecular convergence, a newly duplicated KCNQ gene acquired the property of selective axonal targeting by mimicking a motif present on the sodium channel. This sharing establishes an essential balance conserved in all vertebrates between restraint (mediated by KCNQ channels) and excitability (mediated by sodium channels). This balance ensures proper action potential initiation and saltatory conduction. Loss of this balance leads to epilepsy.
KCNQ2/3 encephalopathy: mechanisms, models, and new therapies
Human KCNQ2 and KCNQ3 mutations cause a spectrum of disease phenotypes, including a transient form of neonatal epilepsy, peripheral nerve hyperexcitability manifesting as muscle twitches, and severe epilepsy with profound intellectual disability (epileptic encephalopathy). We have established a KCNQ2/3 case registry and locus specific database, and are leading a multidisciplinary international variant curation effort. In the lab, we are analyzing the basis for KCNQ2/3 genotype-phenotype relationships through multidisciplinary studies combining protein immunolocalization, electrophysiology in cultured cells, neurons and in vivo, and computational modeling. We are testing strategies for reversing the effects of KCNQ2 mutations as treatments in cases with persistent epilepsy and developmental delay.
ANK3-related mechanisms in epilepsy and psychiatric disease
We first showed that KCNQ channel clustering on axons depends on interaction with ankyrin-G, a large adaptor protein, encoded by a very complex gene, ANK3. Recently, variation at ANK3 has been implicated in epilepsy, autism, schizophrenia, and bipolar disorder. We have begun new work analyzing the molecular diversity of ankyrin-G isoforms, based on the hypothesis that altered expression of particular isoforms contributes to ANK3’s association with disease.
Comprehensive list of publications and presentations
- Xu M, Cooper EC "An Ankyrin-G N-terminal gate and protein kinase CK2 dually regulate binding of voltage-gated sodium and KCNQ2/3 potassium channels." J Biol Chem.. 2015 July 3; 290 : 16619-32. Pubmed PMID: 25998125
- Martinello K, Huang Z, Lujan R, Tran B, Watanabe M, Cooper EC, Brown DA, Shah MM "Cholinergic afferent stimulation induces axonal function plasticity in adult hippocampal granule cells." Neuron. 2015 January 21; 85 : 346-63. Pubmed PMID: 25578363
- Ho TS, Zollinger DR, Chang KJ, Xu M, Cooper EC, Stankewich MC, Bennett V, Rasband MN "A hierarchy of ankyrin-spectrin complexes clusters sodium channels at nodes of Ranvier." Nat Neurosci. 2014 December ; 17 : 1664-72. Pubmed PMID: 25362473
- Kang S, Xu M, Cooper EC, Hoshi N "Channel anchored protein kinase CK2 and protein phosphatase 1 reciprocally regulate KCNQ2-containing M-channels via phosphorylation of calmodulin.." J Biol Chem.. 2014 April 18; 289 (16): 11536-44. Pubmed PMID: 24627475
- Battefeld A, Tran BT, Gavrilis J, Cooper EC, Kole MHP "Heteromeric Kv7.2/Kv7.3 Channels in neocortical myelinated axons regulate action potential initiation and conduction." J Neurosci.. 2014 34 (10): 3719-32. Pubmed PMID: 24599470
- Millichap JJ, Cooper EC "KCNQ2 Potassium Channel Epileptic Encephalopathy Syndrome: Divorce of an Electro-Mechanical Couple?." Epilepsy Curr. 2012 July ; 12 (4): 150-2. Pubmed PMID: 22936888
- Cooper EC "Made for anchorin": Kv7.2/7.3 (KCNQ2/KCNQ3) channels and the modulation of neuronal excitability in vertebrate axons."." Semin. Cell Dev. Biol.. 2011 April ; 22 (2): 185-92. Pubmed PMID: 20940059
- Raol YH, Lapides DA, Keating JG, Brooks-Kayal AR, Cooper EC "A KCNQ channel opener for experimental neonatal seizures and status epilepticus.." Ann. Neurol.. 2009 March ; 65 (3): 326-36. Pubmed PMID: 19334075
- Hill AS, Nishino A, Nakajo K, Zhang G, Fineman JR, Selzer ME, Okamura Y, Cooper EC "Ion channel clustering at the axon initial segment and node of Ranvier evolved sequentially in early chordates.." PLoS Genet.. 2008 December ; 4 (12): e1000317. Pubmed PMID: 19112491
- Shah MM, Migliore M, Valencia I, Cooper EC, Brown DA "Functional significance of axonal Kv7 channels in hippocampal pyramidal neurons.." Proc. Natl. Acad. Sci. U.S.A.. 2008 June 3; 105 (22): 7869-74. Pubmed PMID: 18515424
- Pan Z, Kao T, Horvath Z, Lemos J, Sul JY, Cranstoun SD, Bennett V, Scherer SS, Cooper EC "A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon.." J. Neurosci.. 2006 March 8; 26 (10): 2599-613. Pubmed PMID: 16525039
- Schwarz JR, Glassmeier G, Cooper EC, Kao TC, Nodera H, Tabuena D, Kaji R, Bostock H "KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier.." J. Physiol. (Lond.). 2006 May 15; 573 : 17-34. Pubmed PMID: 16527853
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