Rajesh Khanna, Ph.D.
Associate Professor, Department of Pharmacology & Toxicology
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.
1. Ju W, Li Q, Wilson SM, Brittain JM, Meroueh L, Khanna R*. SUMOylation alters CRMP2 regulation of calcium influx in sensory neurons. Channels (Austin) 7 May/June 2013 Channels (Austin). 2013 Mar 19;7(3). [Epub ahead of print] PMID: 23510938 [work performed at IUSM]
2. Mani T, Wang F, Knabe W, Sinn A, Khanna M, Jo I, Sandusky G, Sledge G, Jones D, Khanna R, Pollok K, Meroueh S. Small-Molecule Probing the Urokinase Receptor in Breast Cancer Lung Metastasis. Bioorganic & Medicinal Chemistry. (Accepted Dec. 20, 2012) DOI: http://dx.doi.org/10.1016/j.bmc.2012.12.047 [work performed at IUSM]
3. Park K, Wang Y, Yang X-F, Lee H, Dustrude ET, Khanna R*, Kohn, H*. Discovery of Lacosamide Affinity Bait Agents That Exhibit Potent Voltage-Gated Sodium Channel Blocking Properties. ACS Chemical Neuroscience (Accepted, in press) DOI: 10.1021/cn300188h *co-corresponding author [work performed at IUSM]
4. Brittain JM, Wang Y, Eruvwetere O, Khanna R*. Cdk5-mediated phosphorylation of CRMP-2 enhances its interaction with CaV2.2. FEBS Lett. 2012 Nov 2;586(21):3813-8. doi: 10.1016/j.febslet.2012.09.022. Epub 2012 Sep 26. PubMed PMID: 23022559. *corresponding author [work performed at IUSM]
5. Ju W, Li Q, Allette YM, Ripsch MS, White FA, Khanna R*. Suppression of pain-related behavior in two distinct rodent models of peripheral neuropathy by a homopolyarginine-conjugated CRMP2 peptide. J Neurochem. 2012 Oct 26. doi:10.1111/jnc.12070. [Epub ahead of print] PubMed PMID: 23106100. *corresponding author [work performed at IUSM]
6. Khanna R*, Wilson SM, Brittain JM, Weimer J, Sultana R, Hensley K. Opening Pandora’s Jar: a Primer on the Putative Roles of Collapsin Response Mediator Protein 2 (CRMP2) in a Panoply of Neurodegenerative, Sensory and Motor Neuron, and Central Disorders. Future Neurol. (2012) 7(6), 749–771 *corresponding author [work performed at IUSM]
7. Feldman P, Due MR, Ripsch MS, Khanna R, White FA. The persistent release of HMGB1 contributes to tactile hyperalgesia in a rodent model of neuropathic pain. J Neuroinflammation. 2012 Jul 23;9:180. doi: 10.1186/1742-2094-9-180. PubMed PMID: 22824385; PubMed Central PMCID: PMC3488576. [work performed at IUSM]
8. Wilson SM, Schmutzler BS, Brittain JM, Ripsch MS, Hingtgen CM, White FA, Khanna R*. Inhibition of Transmitter Release and Attenuation of AIDS Therapy-Induced Painful Peripheral Neuropathy by Synthetic Ca2+ Channel Peptides. J Biol Chem. 2012 Oct 12;287(42):35065-77. doi:10.1074/jbc.M112.378695. Epub 2012 Aug 13. PubMed PMID: 22891239; PubMed Central PMCID: PMC3471755. *corresponding author [work performed at IUSM]
9. Piekarz AD, Due MR, Khanna M, Wang B, Ripsch MS, Meroueh SO, White FA, Khanna R*. CRMP-2 Peptide Mediated Decrease of T- and R-type Voltage-Activated Calcium Channels Contributes to Attenuation of Nociceptor Excitability and Anti-nociception in a Model of AIDS Therapy-Induced Painful Peripheral Neuropathy. Mol Pain. 2012 Jul 24;8(1):54. [Epub ahead of print] PubMed PMID: 22828369. *corresponding author [work performed at IUSM]
10. Due MR, Feldman P, Wilson N, Ripsch MS, Chavez S, Yin M, Khanna R, White FA. Neuroexcitatory effects of morphine-3-glucuronide are dependent on Toll-like receptor 4 signaling. J Neuroinflammation. 2012 Aug 16;9(1):200. [Epub ahead of print] PubMed PMID: 22898544. [work performed at IUSM]
11. Brittain MK, Broustovetsky T, Brittain JM, Khanna R, Broustovetsky, N. Ifenprodil, a NR2B-selective antagonist of NMDA receptor, inhibits reverse Na+/Ca2+ exchanger in neurons. Neuropharmacology. 2012 Nov;63(6):974-82. doi:10.1016/j.neuropharm.2012.07.012. Epub 2012 Jul 20. PubMed PMID: 22820271; PubMed Central PMCID: PMC3427421. [work performed at IUSM]
12. King AN, Wang Y, Brittain JM, Wilson SM, Salome C, Khanna R*, and Kohn H*. (2012) Structure-function analysis of vicinal diamine anticonvulsants: Elucidation of structural templates for potent sodium channel neurological agents. ACS Chemical Neuroscience (December 2012, in press) *co-corresponding author [work performed at IUSM]
13. Sarah M. Wilson, Wenhui Xiong, Yuying Wang, Xingjie Ping, Jessica D. Head, Joel M. Brittain, Pravin D. Gagare, P. Veeraraghavan Ramachandran, Xiaoming Jin, and Rajesh Khanna* (2012) Prevention of posttraumatic axon sprouting by blocking CRMP2-mediated neurite outgrowth and tubulin polymerization. Neuroscience. 2012 May 17;210:451-66. Epub 2012 Feb 28. PubMed PMID: 22433297; PubMed Central PMCID: PMC3358479. *corresponding author [work performed at IUSM]
14. Ripsch MS, Ballard CJ, Khanna M, Hurley JH, White FA, Khanna R* (2012) A peptide uncoupling CRMP-2 from the presynaptic Ca2+ channel complex demonstrates efficacy in animal models of migraine and AIDS therapy-induced neuropathy. Transl. Neurosci. 2012 Mar 3(1):1-8. PubMed PMID: 22662308; PubMed Central PMCID: PMC3365854. *corresponding author [work performed at IUSM]
15. Brittain JM, Wang T, Wilson SM, Khanna R* (2012) Regulation of CREB signaling through L-Type Ca2+ channels by Nipsnap-2. Channels (Austin). 2012Mar-Apr;6(2):94-102. doi: 10.4161/chan.19415. Epub 2012 Mar 1. PubMed PMID:22627147. *corresponding author [work performed at IUSM]