Michael Thomas Klein, Ph.D.
Research Fellow
B.S. State University of New Yorkat Albany, 2006
Biochemistry & Molecular Biology
Ph.D. Albany Medical College, Union University, 2011
Neuropharmacology & Neuroscience
Biosketch and Research Interests
Michael Klein, Ph.D., joined the Conn laboratory in 2011 as a postdoctoral research fellow. Michael undertook his doctoral training in the laboratory of a leading serotonin (5-HT) and G-protein coupled receptor (GPCR) researcher, Prof. Milt Teitler, at Albany Medical College in New York State. Under Prof. Teitler’s supervision, Michael conducted his dissertation research on the 5-HT1E receptor, identifying the distribution of 5-HT1E receptors in the mammalian brain, establishing the guinea big as the first pre-clinical animal model for the study of this receptor, and pursuing the development of subtype-selective drugs for the 5-HT1E receptor in collaboration with Prof. Richard Glennon of Virginia Commonwealth University. Additionally, Michael extensively studied the novel GPCR-inactivating properties of anti-psychotics and other drugs that act at 5-HT2A, 5-HT7, and dopamine D2 receptors. This work revealed for the first time how protomer-protomer allosteric interaction of GPCR homo- or heterodimers could be modulated by small molecule ligands and demonstrated the utility of drugs that take advantage of the dimeric nature of GPCRs.
In the Conn lab, Michael continues to pursue his interests in GPCR biology and his interest in the development of drugs that act through GPCRs expressed in the brain. Michael’s studies focus on the M4 muscarinic acetylcholine receptor. The neurotransmitter acetylcholine signals through ion channels, termed nicotinic acetylcholine receptors, and GPCRs, termed muscarinic acetylcholine receptors. While the M4 receptor has been canonically defined as a Gi/o-coupled receptor, Michael is investigating the possible coupling of M4 receptors to other G-protein and β-arrestin-mediated signaling pathways. This investigation will directly inform M4 drug development efforts in the Conn lab. Having previously shown that activation of brain-expressed M4 receptors promotes anti-psychotic effects in rats, the Conn lab is pursuing M4-selective positive allosteric modulators (PAMs) as potential therapeutics for the treatment of disorders characterized by cognitive disturbances (e.g. schizophrenia). PAMs potentiate agonist activity but lack the ability to stimulate receptor activity on their own, and although allosteric modulators may have advantages over traditional orthosteric drugs, these compounds have the potential to greatly complicate our understanding of receptor pharmacology. Michael’s project aims to understand how the interaction of allosteric modulators with the M4 receptor differentially affects signaling cascades mediated by this receptor. The identification of allosteric modulators that bias M4- signaling may help to elucidate the relevant signaling pathways responsible for the M4 receptor’s anti-psychotic role in vivo. Michael believes that drug candidates can be identified that bias acetylcholine’s activity at M4 receptors towards therapeutically relevant signaling pathways, potentially reducing deleterious side effects. This emphasis on developing allosteric modulators that bias acetylcholine’s engagement of M4-mediated signaling pathways will help to propagate a more nuanced appreciation of cholinergic activity in the brain and refine our ideas concerning GPCR signaling properties.
Selected Publications
Klein M.T. and Teitler M. (in press) Distribution of 5-HT1E receptors in the mammalian brain and cerebral vasculature: an immunohistochemical and pharmacological study. British Journal of Pharmacology.
Teitler M. and Klein M.T. (2011) A new approach for studying GPCR dimers: drug-induced inactivation and reactivation to reveal GPCR dimer function in vitro and in vivo. Pharmacology & Therapeutics, Epub ahead of print. PMID: 22119169.
Klein M.T., Dukat M., Glennon R.A., and Teitler M. (2011) Towards selective drug development for the human 5-HT1E receptor: a comparison of 5-HT1E and 5-HT1F receptor structure-affinity relationships. Journal of Pharmacology and Experimental Therapeutics, 337(3):860-867. PMID: 21422162.
Klein M.T. and Teitler M. (2011) Antagonist interaction with the human 5-HT7 receptor mediates the rapid and potent inhibition of non-G-protein-stimulated adenylate cyclase activity: a novel GPCR effect. British Journal of Pharmacology, 162(8):1843-1854. PMID: 21198551.
Klein M.T. and Teitler M. (2009) Guinea pig hippocampal 5-HT1E receptors: a tool for selective drug development. Journal of Neurochemistry, 109(1):268-274. PMID: 19200348.
