Rajesh Khanna

Rajesh Khanna

Professor, Anesthesiology
Professor, BIO5 Institute
Professor, Neuroscience - GIDP
Professor, Pharmacology
Primary Department
Department Affiliations
(520) 626-4281

Work Summary

Work Summary
The focus of my laboratory’s’ research is to understand how ion channels, specifically, voltage-gated calcium and sodium channels, are regulated by novel protein interactions. Recent studies in my laboratory have focused on targeting protein-protein interactions with biologics (peptide aptamers) and small molecules; testing the activity of these novel chemical entities in biochemical and immunofluorescent-based assays of trafficking; examining their protein interaction signatures; testing them with whole cell voltage-clamp electrophysiology and voltage- and calcium sensitive fluorescence-based imaging. Regulating these protein networks to modulate the activity of ion channels in neurodegenerative diseases (Chronic Pain, Migraine, and Neurofibromatosis) is a key focus of the laboratory.

Research Interest

Research Interest
Regulation of Trafficking and Functions of Voltage-Gated Sodium and Calcium Channels; Identification of Novel Protein Regulators of Ion channels; Approaches to Targeting the Ion Channel Complexes in Neuropathic Pain and Neurodegenerative Diseases; Discovery of Novel Biologics and Small Molecules Targeting Pain and Neurodegenerative Diseases


Brittain, J. M., Piekarz, A. D., Wang, Y., Kondo, T., Cummins, T. R., & Khanna, R. (2009). An atypical role for collapsin response mediator protein 2 (CRMP-2) in neurotransmitter release via interaction with presynaptic voltage-gated calcium channels. The Journal of biological chemistry, 284(45), 31375-90.

Collapsin response mediator proteins (CRMPs) specify axon/dendrite fate and axonal growth of neurons through protein-protein interactions. Their functions in presynaptic biology remain unknown. Here, we identify the presynaptic N-type Ca(2+) channel (CaV2.2) as a CRMP-2-interacting protein. CRMP-2 binds directly to CaV2.2 in two regions: the channel domain I-II intracellular loop and the distal C terminus. Both proteins co-localize within presynaptic sites in hippocampal neurons. Overexpression in hippocampal neurons of a CRMP-2 protein fused to enhanced green fluorescent protein caused a significant increase in Ca(2+) channel current density, whereas lentivirus-mediated CRMP-2 knockdown abolished this effect. Interestingly, the increase in Ca(2+) current density was not due to a change in channel gating. Rather, cell surface biotinylation studies showed an increased number of CaV2.2 at the cell surface in CRMP-2-overexpressing neurons. These neurons also exhibited a significant increase in vesicular release in response to a depolarizing stimulus. Depolarization of CRMP-2-enhanced green fluorescent protein-overexpressing neurons elicited a significant increase in release of glutamate compared with control neurons. Toxin block of Ca(2+) entry via CaV2.2 abolished this stimulated release. Thus, the CRMP-2-Ca(2+) channel interaction represents a novel mechanism for modulation of Ca(2+) influx into nerve terminals and, hence, of synaptic strength.


The novel anti-epileptic drug lacosamide targets two proteins - voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP-2) - suggesting dual modes of action for lacosamide. We recently identified the neurite outgrowth and axonal guidance protein CRMP-2 as a novel partner and regulator of the presynaptic N-type voltage-gated Ca(2+) channel (CaV2.2) [Brittain et al., J. Biol. Chem. 284: 31375-31390 (2009)]. Here we examined the effects of lacosamide on voltage-gated Ba(2+) channels. Lacosamide did not affect Ba(2+) currents via N- and P/Q- channels in rat hippocampal neurons or L-type Ca(2+) channels in a mouse CNS neuronal cell line, respectively. N-type Ba(2+) currents, augmented by CRMP-2 expression, were also unaffected by acute or chronic lacosamide exposure. These results establish that the anti-epileptic mode of action of lacosamide does not involve these voltage-gated Ca(2+) channels.

Khanna, R., Roy, L., Zhu, X., & Schlichter, L. C. (2001). K+ channels and the microglial respiratory burst. American journal of physiology. Cell physiology, 280(4), C796-806.

Microglial activation following central nervous system damage or disease often culminates in a respiratory burst that is necessary for antimicrobial function, but, paradoxically, can damage bystander cells. We show that several K+ channels are expressed and play a role in the respiratory burst of cultured rat microglia. Three pharmacologically separable K+ currents had properties of Kv1.3 and the Ca2+/calmodulin-gated channels, SK2, SK3, and SK4. mRNA was detected for Kv1.3, Kv1.5, SK2, and/or SK3, and SK4. Protein was detected for Kv1.3, Kv1.5, and SK3 (selective SK2 and SK4 antibodies not available). No Kv1.5-like current was detected, and confocal immunofluorescence showed the protein to be subcellular, in contrast to the robust membrane localization of Kv1.3. To determine whether any of these channels play a role in microglial activation, a respiratory burst was stimulated with phorbol 12-myristate 13-acetate and measured using a single cell, fluorescence-based dihydrorhodamine 123 assay. The respiratory burst was markedly inhibited by blockers of SK2 (apamin) and SK4 channels (clotrimazole and charybdotoxin), and to a lesser extent, by the potent Kv1.3 blocker agitoxin-2.

Quach, T. T., Honnorat, J., Kolattukudy, P. E., Khanna, R., & Duchemin, A. M. (2015). Collapsin response mediator protein 3 increases the dendritic arborization of hippocampal neurons. Molecular psychiatry, 20(9), 1027.
Brittain, J. M., Pan, R., You, H., Brustovetsky, T., Brustovetsky, N., Zamponi, G. W., Lee, W., & Khanna, R. (2015). Disruption of NMDAR-CRMP-2 signaling protects against focal cerebral ischemic damage in the rat middle cerebral artery occlusion model. Channels (Austin, Tex.), 6(1), 52-9.

Collapsin response mediator protein 2 (CRMP-2), traditionally viewed as an axon/dendrite specification and axonal growth protein, has emerged as nidus in regulation of both pre- and post-synaptic Ca ( 2+) channels. Building on our discovery of the interaction and regulation of Ca ( 2+) channels by CRMP-2, we recently identified a short sequence in CRMP-2 which, when appended to the transduction domain of HIV TAT protein, suppressed acute, inflammatory and neuropathic pain in vivo by functionally uncoupling CRMP-2 from the Ca ( 2+) channel. Remarkably, we also found that this region attenuated Ca ( 2+) influx via N-methylD-Aspartate receptors (NMDARs) and reduced neuronal death in a moderate controlled cortical impact model of traumatic brain injury (TBI). Here, we sought to extend these findings by examining additional neuroprotective effects of this peptide (TAT-CBD3) and exploring the biochemical mechanisms by which TAT-CBD3 targets NMDARs. We observed that an intraperitoneal injection of TAT-CBD3 peptide significantly reduced infarct volume in an animal model of focal cerebral ischemia. Neuroprotection was observed when TAT-CBD3 peptide was given either prior to or after occlusion but just prior to reperfusion. Surprisingly, a direct biochemical complex was not resolvable between the NMDAR subunit NR2B and CRMP-2. Intracellular application of TAT-CBD3 failed to inhibit NMDAR current. NR2B interactions with the post synaptic density protein 95 (PSD-95) remained intact and were not disrupted by TAT-CBD3. Peptide tiling of intracellular regions of NR2B revealed two 15-mer sequences, in the carboxyl-terminus of NR2B, that may confer binding between NR2B and CRMP-2 which supports CRMP-2's role in excitotoxicity and neuroprotection.