Department of Medicinal Chemistry and Molecular Pharmacology Personnel - Gregory H. Hockerman
Specialization: Molecular pharmacology
EducationB.S. - Olivet Nazarene College, 1983
Ph.D. - University of Wisconsin, 1991
Postdoc - University of Washington, 1991-1997
Research Assistant Professor - University of Washington, 1997-1998
Research: Molecular pharmacology
Voltage-gated calcium channels are key players in a large array of physiological processes including contraction of cardiac, vascular and skeletal muscle, release of neurotransmitters from nerve terminals, gene expression, and hormone secretion. The long-range goal of our studies is to contribute to the development of drugs that can modulate voltage-gated calcium channels in a tissue and type selective manner to treat cardiovascular disease and type II diabetes. Work in our laboratory is focused on two general questions.
Cardiovascular Disease: How do small molecule drugs modulate voltage-gated calcium channels? Three distinct classes of small molecule drugs that modulate L-type calcium channels are currently in clinical use: dihydropyridines (DHP), phenylalkylamines (PAA) and benzothiazepines (BZP). These drugs are used extensively to treat cardiovascular disorders such as hypertension, angina pectoris and some arrhythmias. Using site-directed mutagenesis, expression of recombinant channels in tsA 201 cells, and whole-cell patch-clamp recording techniques, we have identified key amino acid residues for the interaction of each class of drugs with L-type channels. Using this information, we were able to construct a dihydropyridine binding site in a normally DHP-insensitive P/Q- type calcium channel by making only 9 amino acid substitutions. The resulting mutant channel exhibited dihydropyridine modulation nearly identical to that of L-type channels. This result suggests that DHPs may be a useful starting point in the search for calcium channel type selective drugs. Recent work in my lab has centered on describing the binding site for the BZP diltiazem in the Cav1.2 L-type channel, as well as the Ca2+ binding site in the channel that modulates the affinity for diltiazem. We are currently using chemical reagents in conjunction with mutations in the drug binding sites to understand how drug binding modulates channel function.
Type II Diabetes: What roles do L-type calcium channels play in insulin-secreting cells? Drugs acting on L-type calcium channels are used mainly for their effects on the cardiovascular system. L-type channels are, however, located in many tissues outside of the cardiovascular system, most notably in neurons and endocrine cells. Two distinct L-type channels, Cav1.2 and Cav1.3, are often present in the same cells, and distinct roles for each have been difficult to identify, since they are blocked by the same drugs. However, Cav1.2 and 1.3 channels are divergent in regions accessible to the cytoplasm, suggesting distinct roles for these channels in cell signaling. Our current research is focused on the role of Cav1.2 and 1.3 channels in insulin secreting cells. My lab has developed mutant versions of Cav1.2 and 1.3 that are resistant to the DHP class of L-type channel blockers (Cav1.2/DHPi and Cav1.3/DHPi), but normally sensitive to the BZP diltiazem. After introducing these mutant channels into insulin-secreting INS-1 cells, we are able to functionally isolate either Cav1.2 or Cav1.3 channels by "turning off" endogenous L-type channels with the DHP nifedipine. Using this approach, we found that Cav1.3, but not Cav1.2, channels are coupled to glucose-stimulated insulin secretion from INS-1 cells. Further, we found that Cav1.3, but not Cav1.2, channels are coupled to glucose-stimulated oscillations in intracellular Ca2+ concentrations. We are currently testing a series of chimeric Cav1.2/1.3 channels to determine which regions of Cav1.3 are critical for coupling to insulin secretion.
Lab Members:Evan Patrick Sauvie Pratt (PULSe Graduate Student)
Amy Elizabeth Salyer (Technician)
Pratt, E.P.S., Salyer, A.E., Guerra, M.L., and Hockerman, G.H. Ca2+ influx through L-type Ca2+ channels and Ca2+-induced Ca2+ release regulate cAMP accumulation and EPAC1-dependent ERK1/2 activation in INS-1 cells. Mol. Cell. Endocrinol. DOI:10.1016/jmce.2015.09.034 (2015).
Brown, K.M., Roy, K.K., Hockerman, G.H., Doerksen, R.J., and Colby, D.A. Activation of the γ-aminobutyric acid type B (GABAB) receptor by agonists and positive allosteric modulators. J. Med. Chem. 58: 6336-6347 (2015).
Wang, Y., Jarrard, R.E., Pratt, E.P.S., Guerra, M.L., Lange., A.M., Soderling, I.M., Salyer, A.E., Hockerman, G.H. Uncoupling of Cav1.2 from Ca2+-induced Ca2+ release and SK channel regulation in pancreatic β-cells. Mol. Endocrinol. 28: 458-476 (2014).
Han, C., Salyer, A. E., Kim, E. H., Jiang, X., Jarrard, R. E., Powers, M. S., Kirchhoff, A. M., Salvador, T. K., Chester, J. A., Hockerman, G. H., Colby, D. A. Evaluation of Difluoromethyl Ketones as Agonists of the gamma-Aminobutyric Acid Type B (GABA-B) Receptor. J. Med. Chem. 56:2456-2465 (2013).
Jarrard, R.E., Wang, Y., Salyer, A.E, Soderling, I.M., Guerra, M.L., Lange, A.M., Pratt E.P.S., Broderick, H.J. and Hockerman, G.H. Potentiation of sulfonylurea action by an EPAC-selective cAMP analog in INS-1 cells: Comparison of tolbutamide and gliclazide, and a potential role for EPAC activation of a 2-APB-sensitive Ca2+ influx. Mol. Pharmacol. 83: 191-205 (2013).
Lin, M., Aladejebe, O., and Hockerman, G.H. Distinct properties of amlodipine and nicardipine block of the voltage-dependent Ca2+ channels Cav1.2 and Cav2.1 and the mutant channels Cav1.2/DHPi and Cav2.1/DHPs. Eur. J. Pharmacol. 670:105-113 (2011).
Shabbir, W., Beyl, S., Timin, E.N., Schellmann, D., Erker, T., Hohaus, A., Hockerman, G.H., and Hering, S. Interaction of diltiazem with an intracellularly accessible binding site on Cav1.2. Br. J. Pharmacol. 62:1074-1082 (2011).
Jacobo, S.M.P., Guerra, M.L.,and Hockerman, G.H. Cav1.2 and Cav1.3 are differentially coupled to glucagon-like peptide-1 potentiation of glucose-stimulated insulin secretion in the panreatic beta-cell line INS-1 J. Pharmacol. Exp. Ther.331:724-732 (2009).
This record was last updated on Oct 28, 2015 at 1:39 PM