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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 Ca_v1.2 and Ca_v1.3 are closely related, but have distinct distribution, and biophysical properties.  Ca_v1.2 is the predominant Ca²⁺ channel in the cardiovascular system, and Ca_v1.3 is found mainly in neurons and endocrine cells.   We’ve identified 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 specific auxiliary beta subunits using DNA-encoded macrocycle libraries in collaboration with the laboratory of Dr. Casey Krusemark.  Drugs that could selectively inhibit Ca_v1.3 may be useful in the treatment of neurodegenerative diseases, while selective Ca_v1.2 inhibitors may have advantages in the treatment of cardiovascular disease.

Type II Diabetes: What roles do RYR2 and IRBIT play in insulin-secreting cells? Our lab has a long-term interest in understanding the distinct roles of Ca_v1.2 and Ca_v1.3 in insulin secreting cells, pancreatic beta-cells.  Our work thus far supports a role for Ca_v1.3 in initiating glucose-stimulated electrical excitability, and a role for Ca_v1.2 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 Ca_v1.2 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 markedy reduced insulin transcript, content, and secretion in the rat insulinoma cell line INS-1.  In addition, deletion of RyR2 led to reduced levels of the protein IRBIT (a.k.a. Adenosyl homocysteinase-like 1; AHCYL1).  Deletion of IRBIT also reduced insulin transcript, content and secretion, and dysregulated levels of proteins critical for pancreatic beta cell function.  The role of IRBIT in pancreatic beta cells has not been previously studied.  The role of IRBIT in regulating subcellular localization of the enzyme Adenosyl homocysteinase (AHCY) suggests that IRBIT could regulate both DNA and protein methylation.

MCMP 544

PHRM 825

PHRM 844 (Co-coordinator)

IUSM- West Lafayette

Associate Department Head- Medicinal Chemistry and Molecular Pharmacology

Pharmacology Discipline Leader- Indiana University School of Medicine- West Lafayette

Harvey, K.E., Tang, S., LaVigne, E.K., Pratt, E.P.S., Hockerman, G.H. RyR2 regulates store-operated Ca2+ entry, phospholipase C activity, and electrical excitability in the insulinoma cell line INS-1. PLoS ONE 18(5): e0285316. https://doi.org/10.1371/journal.pone.0285316 (2023)

Harvey, K.E., LaVigne, E.K., Dar, M.D., Salyer, A.E., Pratt, E.P.S., Sample, P.A., Aryal, U.K., Gowher, H., Hockerman, G.H. RyR2/IRBIT regulates insulin gene transcript, insulin content, and secretion in the insulinoma cell line INS-1. Sci. Rep. 12(1):7713. doi: 10.1038/s41598-022-11276-8 (2022)

Whitmore, C., Pratt, E.P.S., Anderson, L., Bradley, K., Latour, S.M., Hashmi, M.N., Urazaev, A.K., Weilbaecher, R., Davie, J.K., Wang, W.H., Hockerman, G.H., Pond, A.L. The ERG1A potassium channel increases basal intracellular calcium concentration and calpain activity in skeletal muscle cells. Skeletal Muscle 10: 1 DOI: 10.1186/s13395-019-0220-3 (2020)

Pratt, E.P.S., Harvey, K.E., Salyer, A.E., Hockerman, G.H. Regulation of cAMP accumulation and activity by distinct phosphodiesterase subtypes in INS-1 cells and human pancreatic β-cells. PLoS ONE 14:e0215188 (2019)

Free Download: https://doi.org/10.1371/journal.pone.0215188

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).

Free Download: http://molpharm.aspetjournals.org/cgi/reprint/94/3/973.pdf?ijkey=qpuv5dzghtiVzp3&keytype=finite

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 (GABA_B) 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 Ca_v1.2 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 Ca_v1.2 and Ca_v2.1 and the mutant channels Ca_v1.2/DHPi and Ca_v2.1/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 Ca_v1.2.  Br. J. Pharmacol. 62:1074-1082 (2011).

Jacobo, S.M.P., Guerra, M.L.,and Hockerman, G.H. Ca_v1.2 and Ca_v1.3 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 Ca_v1.2 and Ca_v1.3 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 Ca_v1.2 and Ca_v1.3 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 Ca_v1.2. Mol. Pharmacol.66:1236-1247 (2004)
 
Liu, G., Hilliard, N., and Hockerman, G.H. Preferential coupling of Ca_v1.3 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 Ca_v1.2 Mol. Pharmacol.64:491-501 (2003).
 
Liu, G., Dilmac, N., Hilliard, N., and Hockerman, G.H. Ca_v1.3 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).