Glucose and humoral signaling pathways in islet beta cells.
Glucose activates multiple pathways in the
pancreatic beta cell including Ca2+
influx through voltage dependent Ca2+
channels, phospholipid metabolism, and cAMP generation. Hormonal agonists also activate similar
pathways but by distinct mechanisms. The goal of our laboratory is to elucidate
glucose signaling pathways in the beta cell and identify sites of dysregulation of these pathways in type 2
diabetes mellitus. Specifically, our research has focused on defining
how glucose activates two critical cellular effectors: PI-specific phospholipase C (PLC) and adenylyl
cyclase (AC). We are currently studying a novel PLC, PLC
epsilon, that we have recently cloned, which may play a critical role in islet
beta cell development and function.
Selected Publications:
Chepurny, OG,
Leech CA, Kelley GG, Dzhura I, Dzhura
E, Li X, Rindler MJ, Schweede
F, Genieser HG, Hozl GG. Enhanced Rap1 activation
and insulin secretagogue properties of an acetoxymethyl ester of an Epac-selective
cyclic AMP analog in rat INS-1 cells: Studies with 8-pCPT-2'-O-Me-cAMP-AM. J of Biol Chem,
284:10728-36, 2009.
Oestreich EA, Malik S, Goonasekera SA, Blaxall BC, Kelley GG, Dirksen RT, Smrcka
AV. EPAC and phospholipase
Cepsilon regulate Ca2+ release in the heart by
activation of protein kinase Cepsilon
and calcium-calmodulin-kinaseII. J Biol Chem. 284:1514-22,
2009.
Kaproth-Joslin KA, Li
X, Reks SE, Kelley GG. Phospholipase Cd1 Regulates Cell
Proliferation And Cell Cycle Progression From G1 To S Phase By Control Of Cyclin E/Cdk2 Activity. Biochem
J, 415:439-48, 2008.
Citro, S, Malik S, Oestreich EA, Radeff-Huang J, Kelley GG, Smrcka
AV, Brown JH. Phospholipase Cepsilon
is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation. Proc Natl
Acad Sci USA 104(39):15543-8, 2007
Pearce MM, Wang Y, Kelley GG, Wojcikiewicz RJ. SPFH2 Mediates the Endoplasmic
Reticulum-associated Degradation of Inositol
1,4,5-Trisphosphate Receptors and Other Substrates in Mammalian Cells. JBC
282:20104-15, 2007
Oestreich EA,
Wang H, Malik S, Kaproth-Joslin
KA, Blaxall B, Kelley GG, Dirksen RT, Smrcka AV. Epac-mediated
activation of phopholipase C epsilon plays a critical
role in B-adrenergic receptor-dependent enhancement of Ca2+
mobilization in cardiac myocytes. JBC 282:5488-95,
2007
Hinkes B,
Wiggins RC et al, Positional cloning
uncovers mutations in PLCE1 responsible for a nephrotic
syndrome variant that may be reversible. Nature Genetics, 38(12):1397-1405, 2006.
Kelley GG, Kaproth-Joslin
KA, Reks SE, Smrcka AV, Wojcikiewicz, G protein coupled receptor agonists activate
endogenous phospholipase Ce
and phospholipase Cb3 in a temporally distinct
manner. JBC, 281:2639-2648, 2006
Kelley GG, Reks
SE, Smrcka AV. Hormonal regulation of phospholipase C epsilon through distinct and overlapping
pathways involving G12 and Ras family G proteins. Biochem J. 378:129-139, 2004.
Kelley GG, Reks
S, Ondrako JM, Smrcka
A. Phospholipase
Ce: a novel Ras effector. EMBO
Journal 20(4):1-12, 2001.
