Rajesh Khanna, Ph.D.

Assistant Professor, Department of Pharmacology & Toxicology

Education/Training:
Ph.D.: University of Toronto, Toronto, Ontario, Canada (2000)
Postdoctoral Fellowship: University of California at Los Angeles, CA, USA (2003)
Scientific Associate: Toronto Western Research Institute, Toronto, Ontario, Canada (2007)

CRMPs, novel regulators of calcium homeostasis in health and disease.

My laboratory is attempting to better understand the molecular and mechanistic basis of the roles of ion channels in human health and disease.  In particular, my laboratory’s research aims to study fundamentals of synaptic transmission because improper function and regulation of Ca²⁺ channels and the proteins that regulate them can contribute to epilepsy, migraine, ataxia, and other neurological diseases.  Three projects are currently being pursued in my laboratory:

                In the first project, funded by the American Heart Association National Scientist Development grant, we have focused on studying the effects of collapsin response mediator protein 2 (CRMP-2), a family of proteins involved in neurite outgrowth, guidance, and axonogenesis on voltage-gated calcium (Cav2.2) channels.  Our main objective is to understand the functional impact of this novel interaction between these presynaptic Ca²⁺ channels and CRMPs on synaptic transmission.  As modifying transmitter release is important in altering neuronal functions during development, learning, disease states, and other forms of brain plasticity, our future studies will examine how this interaction can contribute to learning and memory.

                In a second project, funded by the Department of Defense Neurofibromatosis New Investigator Award, we are working on a novel pathway for Neurofibromatosis type I (NF1), an autosomally dominant diseases characterized by the formation of multiple benign and malignant tumors.  People with NF1 often have learning disabilities and other cognitive symptoms.  Our studies have identified a completely new pathway for NF1 signaling.  This novel pathway involves an axonal guidance and growth protein called CRMP-2 which has been shown to function in neuronal differentiation.  The convergence of signaling pathways of CRMP-2 and NF1 has identified several molecular players, kinases in particular, that affect neuronal function.  Our novel discovery of the CRMP-2–Ca²⁺ channel interaction and the NF1-CRMP-2 interaction highlights a novel regulator of synaptic transmission.  Manipulation of glutamatergic transmission may thus represent a unique avenue for NF1 therapy.  Thus, the proposed mapping of the NF1–CRMP-2 interaction may lead to the identification of peptides capable of blocking the modulatory effects of this protein complex on synaptic transmission. 

                In a third project, we have focused on defining how the expression levels of CRMP-2 can influence the effects of a novel anticonvulsant drug lacosamide on Na⁺ channels.  Lacosamide is a novel anticonvulsant drug that acts in a unique manner to inhibit voltage-gated Na⁺ channels as reported last year.  Lacosamide has gained FDA and EEMA approval for adjunctive therapy for partial-onset seizures with or without secondary generalization in patients with epilepsy and is now marketed in the United States and Europe.  In preclinical findings reported by UCB Pharma, another target of action was identified for this drug.  The mechanism of action of lacosamide on this second target – the collapsin response mediator protein 2 (CRMP-2) – remains elusive.  No studies to date have addressed the implications of this potential interaction on the main effect of lacosamide. 

Publications:

Symbols: *corresponding author; **, co-corresponding author; @co-first author; #in rank

Yuying Wang^†, Sarah M. Wilson, Joel M. Brittain, Matthew S. Ripsch, Christophe Salomé, Ki Duk Park, Fletcher A. White, Rajesh Khanna** and Harold Kohn**.   Merging Structural Motifs of Functionalized Amino Acids and α-Aminoamides Results in Novel Anticonvulsant Compounds with Significant Effects on Slow and Fast Inactivation of Voltage-gated Sodium Channels and in the Treatment of Neuropathic Pain.   ACS Chemical Neuroscience.  Publication Date (Web): April 11, 2011. (in press).  **, co-corresponding authors

Wang, Y., and Khanna, R.  Calcium channels are not affected by the anti-epileptic drug lacosamide. Translational Neuroscience (2011; in press).

Tam T Quach, Yuying Wang, Rajesh Khanna, Naura Chounlamountri , Nathalie Auvergnon, Jerome Honnorat and Anne-Marie Duchemin.   Effect of CRMP3 expression on dystrophic dendrites of hippocampal neurons.   Molecular Psychiatry.  2011, 1-2. Feb. 22

Yuying Wang, Ki Duk Park, Christophe Salom, Sarah M. Wilson, James P. Stables, Rihe Liu, Rajesh Khanna**, and Harold Kohn**.  Development and Characterization of Novel Derivatives of the Antiepileptic Drug Lacosamide That Exhibit Far Greater Enhancement in Slow Inactivation of Voltage-Gated Sodium Channels.   ACS Chemical Neuroscience Publication Date (Web): November 24, 2010. (in press) **, co-corresponding authors.

#Wang, Y, Brittain, JM, Wilson, SM, Hingtgen, CM, and Khanna, R.*.  Altered calcium currents and axonal growth in Nf1 haploinsufficient mice.  Translational Neuroscience 2010 2; 1-9.   *corresponding author       

#Wang Y, Brittain JM, Jarecki BW, Park KD, Wilson SM, Wang B, Hale R, Meroueh SO, Cummins TR, Khanna R.*   In silico docking and electrophysiological characterization of lacosamide binding sites on collapsin response mediator protein 2 (CRMP-2) identifies a pocket important in modulating sodium channel slow inactivation.  J. Biol. Chem. 2010.  First Published on June 9, 2010, doi: 10.1074/jbc.M110.128801  PMID: 20538611  *corresponding author   

#Wang, Y, Brittain, JM, Wilson, SM, and Khanna, R.*.  Emerging roles of collapsin response mediator proteins (CRMPs) as regulators of voltage-gated calcium channels and synaptic transmission.  Comm. Integ. Biol. 2010; 3:58-62.  PMID: 20585514  *corresponding author

#Chi, XX, Schmutzler, BS, Wang, Y, Brittain, JM, Hingtgen, CM, Nicol, GD, and Khanna, R.*.  Regulation of N-type voltage-gated calcium (CaV2.2) channels and transmitter release by collapsin response mediator protein-2 (CRMP-2) in sensory neurons. J. Cell Sci. 2009; 23:4351-4362. PMID: 19903690 *corresponding author  

#Brittain, JM, Piekarz, AD, Wang Y, Kondo T, Cummins TR, and Khanna, R.*.  An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated Ca2+ channels. J Biol Chem. 2009; 284:31375-31390.  PMID: 19755421  *corresponding author    

Khanna R., Li Q, Schlichter, L.C., Stanley E.F.  The transmitter release site CaV2.2 channel cluster is linked to an endocytosis coat protein complex. Eur. J. Neurosci. 2007; 26: 560-574.  PMID: 17686037

Khanna R., Li Q, Bewersdorf, J, Stanley E.F.  The presynaptic CaV2.2 channel-transmitter release site core complex. Eur. J. Neurosci. 2007; 26: 547-559.  PMID: 17686036

Khanna R.*, Zougman A., Stanley E.F*. A proteomic screen for presynaptic terminal N-type Ca2+ channel (CaV2.2) binding partners. J. Biochem. Mol. Biol. 2007; 40: 302-314.   *co-corresponding author  PMID: 17562281

Chan A.W. @, Khanna R. @, Li Q., Stanley E.F. Munc18: a presynaptic transmitter release site N type (CaV2.2) Ca2+ channel interacting protein. Channels 2007; 1: 1-10.  @Co-first author; Selected for cover image  PMID: 19170253

Sun L., Li Q., Khanna R., Chan A.W., Wong F., Stanley E.F.  Transmitter release site Ca2+ channel clusters persist at isolated presynaptic terminals.  Eur. J. Neurosci. 2006; 23: 1391-1396.  PMID: 16553800

Khanna R., Sun L., Li Q., Luo L., Stanley E.F.  Long splice variant N type Ca2+ channels are clustered at presynaptic transmitter release sites without modular adaptor proteins.  Neuroscience 2006; 138: 1115-1125.  PMID: 16473471

Khanna R., Li Q., Sun L., Collins T. J., Stanley E.F.  N type Ca2+ channels and RIM scaffold protein covary at the presynaptic transmitter release face but are components of independent protein complexes.  Neuroscience 2006; 140: 1201-1208.  Selected for cover image  PMID: 16757118

Khanna R., Li Q. Stanley E.F. Fractional recovery analysis of a synaptotagmin-associated complex at the presynaptic transmitter release site. PLoS One 2006; 1: e67 1-9.  PMID: 17183698

Wan J., Khanna R., Sandusky M., Oh F., Baloh R.W., Papazian D.M., Jen J.C.  CACNA1A mutations causing episodic and progressive ataxia alter channel trafficking and kinetics.  Neurology 2005; 64 (12): 2090-2097.  PMID: 15196930

Myers M.P. @, Khanna R@, Lee E.J., Papazian D.M.  Voltage sensor mutations differentially target misfolded K+ channel subunits to proteasomal and non-proteasomal disposal pathways.  FEBS Lett. 2004; 568:110-116.   @Co-first author

Khanna R., Lee E.J., Papazian D.M.  Transient calnexin interaction confers long-term stability on folded K+ channel protein in the ER. J Cell Sci. 2004; 117:2897-2908.  PMID: 15161937

Koni P.A., Khanna R., Chang M.C., Tang M.D., Kaczmarek L.K., Schlichter L.C., Flavell R.A.  Compensatory anion currents in Kv1.3 channel-deficient thymocytes. J Biol Chem. 2003; 278:39443-39451.  PMID: 12878608

Khanna R., Myers M.P., Laine M., Papazian D.M.  Glycosylation increases potassium channel stability and surface expression in mammalian cells. J Biol Chem. 2001; 276:34028-34034.  PMID: 11427541

Joiner W.J.@, Khanna R.@, Schlichter L.C., Kaczmarek L.K.  Calmodulin regulates assembly and trafficking of SK4/IK1 Ca2+-activated K+ channels.  J Biol Chem. 2001; 276:37980-37985.  @Co-first author  PMID: 11495911

Chang M.C., Khanna R., Schlichter L.C.  Regulation of Kv1.3 channels in activated human T lymphocytes by Ca2+-dependent pathways.  Cell Physiol Biochem. 2001; 11:123-134.  PMID: 11410708

Khanna R., Roy L., Zhu X., Schlichter L.C.  K+ channels and the microglial respiratory burst.  Am J Physiol Cell Physiol. 2001; 280:C796-C806.  PMID: 11245596
Chang M.C., Khanna R., Schlichter L.C.  Regulation of Kv1.3 channels in activated human T lymphocytes by Ca2+-dependent pathways.  Cell Physiol Biochem. 2001; 11:123-134.  PMID: 11410708

Cayabyab F.S.@, Khanna R.@, Jones O.T., Schlichter L.C.  Suppression of the rat microglia Kv1.3 current by src-family tyrosine kinases and oxygen/glucose deprivation.  Eur. J. Neurosci. 2000; 12:1949-1960.  @Co-first author  PMID: 10886336

Jugloff D.G., Khanna R., Schlichter L.C, Jones O.T.  Internalization of the Kv1.4 potassium channel is suppressed by clustering interactions with PSD-95.  J Biol Chem. 2000; 275:1357-1364.  PMID: 10625685

Khanna R., Chang M.C., Joiner W.J., Kaczmarek L.K., Schlichter L.C.  hSK4/hIK1, a calmodulin-binding KCa channel in human T lymphocytes. Roles in proliferation and volume regulation.  J Biol Chem. 1999; 274:14838-14849.  PMID: 10329683