Biomedical Research Infrastructure Center

Manju Bhat, M.V.Sc., Ph.D.

Manju Bhat MVSc PhD photoPain is one of the basic human experiences, which can be considered a useful warning sign of an injury, inflammation or infection. However, difficult-to-control, chronic untreated pain resulting from dysfunction of the nervous system (i.e. neuropathic pain) is a significant health problem. Chronic pain is considered a specific healthcare problem and 'a disease in its own right'. About 90% of all illnesses are associated with pain and patients with chronic pain use health services up to five times as frequently as the rest of the population. This is estimated to cost the American public more than $100 billion per year in health care, compensation, litigation, loss of productive work days, etc. Currently, there are no specific treatment options available to manage chronic neuropathic pain, which is commonly associated with nerve injury and diseases such as diabetes, HIV/AIDS, cancer, herpes, etc. This is mainly due to the diverse pathophysiologic mechanisms behind the development and maintenance of pain. The ultimate goal of pain research is to develop novel approaches for effective diagnosis, treatment and management of painful conditions. Dr. Manju Bhat's research is aimed at investigating the mechanisms by which sensory neurons detect and transmit painful signals at the cellular and molecular levels.

Neurophysiology of calcium signaling in sensory neurons: The focus of Dr. Bhat's ongoing research is to study the role of calcium signaling proteins in pain. Calcium is an important ion that is essential for many of our body functions such as skeletal integrity, muscle contraction and neurotransmission (all our brain functions and mind-body coordination). Level of calcium ions inside each of our cell is tightly regulated by specialized calcium transporter proteins (pumps, exchangers and channels). Understanding how cellular calcium homeostasis is maintained and regulated is essential in order to study their possible roles in health and disease. The long-term goal of our research is to identify targets for new and novel pain therapies. Using peripheral sensory neurons grown in culture, we have uncovered the presence of a novel calcium transporting pathway called capacitative calcium entry (CCE), which is present only in pain-conducting (i.e. nociceptive) neurons, but not in normal touch-sensitive (i.e. mechanosensitive) neurons. Selective presence of this calcium entry pathway suggests its importance in the modulation of pain signal transduction. Discovering the identity of this channel and understanding how it functions and what factors regulate its activity will yield useful information about its role in pain. Next step in this research is to study how the activity of these channels is altered under painful conditions. For this, we use experimental models of acute and chronic pain, where we can quantify pain perception and also use molecular methods to measure possible changes in the expression and function of these calcium channels. These approaches will allow us to test new compounds for their ability to control pain.

Anesthetic-mediated regulation of pain: Propofol is an intravenous general anesthetic agent used for both induction and maintenance of anesthesia and for sedation in the intensive care unit. The advantages of propofol's widespread use include its rapid onset and rapid recovery. One of the commonly encountered discomforting effects of propofol during induction of anesthesia is the acute burning sensation at the site of intravenous bolus injection. While the mechanism for propofol-induced pain is not known, it is thought to involve excitation of perivascular sensory nerve endings.

By analyzing the type of sensory cells that are activated and by using cells expressing exogenous genes, Dr. Bhat's research demonstrated that propofol behaves as an activator of vanilloid receptor (TRPV1), which functions as a calcium channel and is a known mediator of pain in response to a variety of noxious stimuli such as heat, acid and the chemical capsaicin. This discovery and our ongoing experiments have several clinical implications with respect to pain medicine. First, by understanding the mechanism(s) by which propofol activates TRPV1 receptor, it will be possible to include a selective TRPV1 receptor antagonist to the propofol formulation routinely used during surgery. This will prevent the discomforting effect of burning pain prior to patient being anesthetized with propofol. Second, propofol can serve as a useful experimental tool to study the function and regulation of TRPV1 receptor, which has recently attracted attention as a key mediator of both acute and chronic pain and hence a target for new painkillers. Third, knowledge of how propofol interacts with the TRPV1 receptor can be used to design and develop propofol "like" molecules that function as TRPV1 receptor blockers instead of activators. These can then safely be used as analgesics after appropriate clinical trials.

The focus of Dr. Bhat's ongoing research is to investigate the mechanisms by which propofol (and some of its chemical cousins) interact with and activate TRPV1 receptor thereby inducing pain. Thus, investigation into the molecular mechanisms by which propofol affects sensory signal transduction will not only help to prevent acute pain during induction of anesthesia, but also will help design new specific drugs to treat chronic pain, for which currently there are no specific treatment options available.

We use combination of cell and molecular biological and imaging techniques to understand the calcium signaling pathways in sensory neurons, and animal models to examine the role of calcium channels in acute and chronic pain.

Manju Bhat, M.V.Sc., Ph.D. Publications

Manjunatha B. Bhat, Jiying Zhao, Hiroshi Takeshima, and Jianjie Ma. (1997). Functional calcium release channel formed by the carboxyl-terminal portion of ryanodine receptor. Biophys. J. 73: 1329-1336.>

Manjunatha B. Bhat, Jiying Zhao, Salim Hayek, Eric C. Freeman, Hiroshi Takeshima, and Jianjie Ma. (1997). Deletion of a.a. 1641-2437 from the foot region of skeletal muscle ryanodine receptor alters conduction properties of the calcium release channel. Biophys. J. 73: 1320-1328.

Manjunatha B. Bhat, Jiying Zhao, Weijin Zang, C. William Balke, Hiroshi Takeshima, W. Gil Wier, and Jianjie Ma. (1997). Caffeine-induced release of intracellular calcium from Chinese hamster ovary cells expressing skeletal muscle ryanodine receptor: Effects on full-length and carboxyl-terminal portion of calcium release channel. J. Gen. Physiol. 101: 749-762.

Manjunatha B. Bhat, Salim M. Hayek, Jiying Zhao, Weijin Zang, Hiroshi Takeshima, Gil Wier, and Jianjie Ma. (1999). Expression and functional characterization of the cardiac muscle ryanodine receptor calcium release channel in CHO cells. Biophys. J. 77: 808-816.

Xuehong Xu, Manjunatha B. Bhat, Miyuki Nishi, Hisoshi Takeshima, and Jianjie Ma (2000). Molecular cloning of cDNA encoding the Drosophila ryanodine receptor and functional studies of the carboxyl-terminal calcium release channel. Biophys. J. 78: 1270-1281.>

Salim M. Hayek, Xinsheng Zhu, Manjunatha B. Bhat, Jiying Zhao, Hiroshi Takeshima, Hector H. Valdivia, and Jianjie Ma. (2000). Characterization of a calcium regulation domain of the skeletal muscle ryanodine receptor. Biochem. J. 351: 57-65.>

Jerry E. Chipuk, Manjunatha B. Bhat, Andrew Y. Hsing, Jianjie Ma, and David Danielpour (2001). Bcl-xL blocks TGF-b1-induced apoptosis by inhibiting cytochrome C release and not by directly antagonizing Apaf-1-dependent caspase activation in prostate epithelial cells. J. Biol. Chem. 276: 26614-26621.

Manjunatha B. Bhat, and Jianjie Ma. (2002). The transmembrane segment of ryanodine receptor contain an intracellular membrane retention signal for Ca2+ release channel. J. Biol. Chem. 277: 8597-8601.

Kalanithee Paul-Pletzer, Takeshi Yamamoto, Manjunatha B. Bhat, Jianjie Ma, Noriaki Ikemoto, Leslie S. Jimenez, Hiromi Morimoto, Philip G. Williams, and Jerome Parness. (2002). Partial mapping of the dantrolene-binding site on the skeletal muscle ryanodine receptor. J. Biol. Chem. 277: 34918-34923.

Dong Wook Shin, Zui Pan, Eun Kyung Kim, Jae Man Lee, Manjunatha B. Bhat, Jerome Parness, Do Han Kim, and Jianjie Ma. (2003). A retrograde signal from calsequestrin for the regulation of store-operated Ca2+ entry in skeletal muscle. J. Biol. Chem. 278: 3286-3292.

Mary L. Ruehr, Mary A. Russell, Donald G. Ferguson, Manjunatha B. Bhat, Jianjie Ma, Derek S. Damron, John D. Scott, and Meredith Bond. (2003). Targeting of PKA by mAKAP regulates phosphorylation and function of the skeletal muscle ryanodine receptor. J. Biol. Chem. 278: 24831-24836.

Sravan Mandadi, Mistuko Numazaki, Makoto Tominaga, Manjunatha B. Bhat, Patricia J. Armati, and Basil D. Roufogalis. (2004). Activation of protein kinase C reverses capsaicin-induced calcium dependent desensitization of TRPV1 ion channels. Cell Calcium. 35: 471-478.

Zui Pan, Yutaka Hirata, Ramakrishnan Y. Nagaraj, Jiying Zhao, Miyuki Nishi, Salim M. Hayek, Manjunatha B. Bhat, Hiroshi Takeshima, and Jianjie Ma. (2004). Co-expression of mg29 and ryanodine receptor leads to apoptotic cell death-effect mediated by intracellular Ca2+ release. J. Biol. Chem. 279: 19387-19390.

Ram H. Nagaraj, Tomoko Oya-Ito, Manjunatha B. Bhat, and Bingfen Liu. (2005). Dicarbonyl stress and apoptosis of vascular cells: prevention by alpha-B-crystallin. Ann. N.Y. Acad. Sci. 1043: 158-165.

Ashis Biswas, Antonia Miller, Tomoko Oya-Ito, Puttur Santhoshkumar, Manjunatha B. Bhat, and Ram H. Nagaraj. (2006). Effect of site-directed mutagenesis of methylglyoxal modifiable arginine residues on the structure and chaperone function of human a A-crystallin. Biochem. 45: 4569-4577.

Antonia G. Miller, Dawn G. Smith, Manjunatha B. Bhat, and Ram H. Nagaraj. (2006). Glyoxalase I is critical for human retinal capillary pericyte survival under hyperglycemic conditions. J. Biol. Chem. 281: 11864-11871.

Sanjoy K. Bhattacharya, Manjunatha B. Bhat, and Hidenari Takahara. (2007). Calcium modulation of peptidyl arginine deaminase 2 and implication for neurodegeneration. Exp. Eye. Res. 31: 1063-1071.

Ashis Biswas, Jeffery Goshe, Antonia G. Miller, Puttur Santhoshkumar, Manjunatha B. Bhat, and Ram H. Nagaraj. (2007). Paradoxical Effects of Substitution and Deletion Mutation of Arg56 on the Structure and Chaperone Function of Human a B-crystallin. Biochem. 46: 1117-1127.

ChangWoo Lee, Si Ae Hwang, Sei-Heon Jang, Manjunatha B. Bhat, and Sadashiva S. Karnik. (2007). Manifold active-state conformations in GPCRs: Agonist-activated constitutively active mutant AT1 receptor preferentially couples to Gq compared to the wild-type AT1 receptor. FEBS Lett. 581: 2517-2522.

Stewart, R., Song, L., Carter, SM, Sigalas, C., Zaccai, NR, Kanamarlapudi, V., Bhat, MB, Takeshima, H. & Sitsapesan, R. (2008). Single-channel characterization of the rabbit recombinant RyR2 reveals a novel inactivation property of physiological concentrations of ATP. J. Membrane Biol. 222: 65-67.

Chaudhuri, P., Colles, SM, Bhat, MB, Van Wagoner, DR, Birnbaumer, L., & Graham, LM. (2008). Elucidation of TRPC6-TRPC5 channel cascade that restricts endothelial cell movement. Mol. Biol. Cell. (In Press)

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