Gregory H. Hockerman
Professor of Medicinal Chemistry and Molecular Pharmacology
Ph.D. - University of Wisconsin, 1991
Postdoc - University of Washington, 1991-1997
Research Assistant Professor - University of Washington, 1997-1998
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 and Neurological disease and type II diabetes. Work in our laboratory is focused on two general questions.
Cardiovascular and Neurological Disease: Subtype-selective modulation of L-type voltage-gated Ca2+ channels The L-type voltage-gate Ca2+ channels Cav1.2 and Cav1.3 are closely related, but have distinct distribution, and biophysical properties. Cav1.2 is the predominant Ca2+ channel in the cardiovascular system, and Cav1.3 is found mainly in neurons and endocrine cells. We’ve recently reported the molecular basis for the small difference in the potency of modulation of these channels by the channel blocker nifedipine, and the channel activator FPL 64176. We’re pursuing a unique approach to discover selective inhibitors of these channels by targeting discrete, extracellular domains of each channel using DNA-encoded macrocycle libraries in collaboration with the laboratory of Dr. Casey Krusemark. Drugs that could selectively inhibit Cav1.3 may be useful in the treatment of neurodegenerative diseases, while selective Cav1.2 inhibitors may have advantages in the treatment of cardiovascular disease.
Type II Diabetes: What roles do L-type calcium channels play in insulin-secreting cells? Our lab has a long-term interest in understanding the distinct roles of Cav1.2 and Cav1.3 in insulin secreting cells, pancreatic beta-cells. Our work thus far supports a role for Cav1.3 in initiating glucose-stimulated electrical excitability, and a role for Cav1.2 in regulating action potential frequency. Our current emphasis is on understanding a process called Ca2+-induced Ca2+ release (CICR) in which influx of Ca2+ via Cav1.2 activates further release of Ca2+ from the endoplasmic reticulum (ER) via a Ca2+-activated channel, the ryanodine receptor 2 (RYR2). Using CRISPR/Cas9 gene editing, we’ve shown that deletion of RYR2 decreases basal cAMP levels, and basal and stimulated insulin secretion in the rat beta-cell line INS-1. Our lab is exploring the role of scaffolding proteins in bringing Cav1.2 and RYR2 into close proximity, which is necessary for CICR. Finally, the lab is developing expertise in differentiation of human inducible pluripotent stem cells (iPSCs) into pancreatic beta-cells, so we can apply CRISPR/Cas9 gene editing to the study of human beta-cells.
IUSM- West Lafayette
Administration and Committee Work
Associate Department Head- Medicinal Chemistry and Molecular Pharmacology
Pharmacology Discipline Leader- Indiana University School of Medicine- West Lafayette
Wang, Y., Tang, S., Harvey, K.E., Salyer, AE., Li, T.A., Rantz, E.K., Lill, M.A., and Hockerman, G.H. Molecular determinants of the differential modulation of Cav1.2 and Cav1.3 by nifedipine and FPL 64176 Mol. Pharmacol 94: 973-983 (2018).
Sowaileh, M.F., Salyer, A.E., Roy, K.K., John, J.P., Woods, J.R., Doerksen, R.J., Hockerman, G.H., and Colby. D.A. Agonists of the gamma-aminobutyric acid type B (GABA-B) receptor derived from beta-hydroxy and beta-amino difluoromethyl ketones Bioorg. Med Chem. Lett. 28:2697-2700 (2018).
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. 419: 60-71 (2016).
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).
Jacobo, S.M.P., Guerra, M.L., Jarrard, R.E., Przybyla, J.A., Liu, G., Watts, V.J., and Hockerman, G.H. The intracellular II-III loops of Cav1.2 and Cav1.3 uncouple L-type voltage-gated Ca2+ channels from glucagon-like peptide-1 potentiation of insulin secretion in INS-1 cells via displacement from lipid rafts J. Pharmacol. Exp. Ther.330:283-293 (2009).
Walsh, K.B., Zhang, J., Fuseler, J.W., Hilliard, N., and Hockerman, G.H. Adenoviral-mediated expression of dihydropyridine-insensitive L-type calcium channels in cardiac ventricular myocytes and fibroblasts Eur. J. Pharmacol. 565:7-16 (2007).
Liu, G., Jacobo, S.M.P., Hilliard, N., and Hockerman, G.H. Cyclic AMP potentiates coupling of both Cav1.2 and Cav1.3 to glucose-stimulated insulin secretion at sub-maximal glucose concentration through EPAC and PKA in INS-1 cells. J. Pharmacol. Exp. Ther.318:152-160 (2006).
Dilmac, N., Hilliard, N., and Hockerman, G.H. Molecular determinants of frequency-dependence and Ca2+ potentiation of verapamil block in the pore region of Cav1.2. Mol. Pharmacol.66:1236-1247 (2004)
Liu, G., Hilliard, N., and Hockerman, G.H. Preferential coupling of Cav1.3 to glucose-induced [Ca2+]i in the pancreatic beta cell line INS-1. Mol. Pharmacol.65:1269-1277 (2004).
Dilmac, N., Hilliard, N., and Hockerman, G.H. Molecular determinants of Ca2+ potentiation of diltiazem block and Ca2+-dependent inactivation in the pore region of Cav1.2 Mol. Pharmacol.64:491-501 (2003).
Liu, G., Dilmac, N., Hilliard, N., and Hockerman, G.H. Cav1.3 is preferentially coupled to glucose-stimulated insulin secretion in the pancreatic beta cell line INS-1. J. Pharmacol. Exp. Ther.305, 271-278 (2003).
Hockerman, G.H., Dilmac, N., Scheuer, T., and Catterall, W.A. Molecular determinants of diltiazem block in domains IIIS6 and IVS6 of L-type calcium channels. Mol. Pharmacol.58, 1264-1270 (2000).