Gender	Female
E-mail	maria.diverse@mssm.edu
Education and Training	Ph.D., University of Massachusetts at Amherst
	M.S., Purdue University
	B.S., Catholic University of Puerto Rico

Diverse-Pierluissi Laboratory

Education and Training	Ph.D., University of Massachusetts at Amherst
	M.S., Purdue University
	B.S., Catholic University of Puerto Rico

Summary of Research Studies:
Voltage-dependent calcium channels are well-known targets for inhibition by a wide range of G protein-coupled receptors (GPCRs). The molecular entities and mechanisms that control the rate-limiting steps underlying the onset and the termination of receptor-mediated channel modulation are not fully understood. My laboratory studies the integration of the multiple signaling pathways that converge to modulate calcium channel activity and how they could ultimately alter the timing of signaling in the nervous system.

The overall goal of my laboratory is to identify the components of signaling complexes regulating calcium channel function, and to understand how interactions of these components with the calcium channel determine the time course of transmitter-mediated inhibition of calcium influx in neurons. We are chick dorsal root ganglion (DRG) neurons which express only one type of voltage-dependent calcium channel, Cav2.2 channels (w-conotoxin GVIA sensitive N-type calcium c! hannel). This system displays multiple mechanisms of G protein-mediated modulation of channel function such as: the G alpha-mediated, G-beta-gamma, tyrosine kinase-mediated and direct G protein regulation of channel. We have described a new mechanism of desensitization at the level of the Cav2.2 channel. Tyrosine kinases can act both as "on" and "off" molecular switches within the G protein pathway. During onset of the response, Src kinase phosphorylates the alpha subunit of the calcium channel. The tyrosine-phosphorylated calcium channel becomes a target for binding of the phosphotyrosine-binding (PTB) domain of RGS12. Our results suggest that RGS12 is a multifunctional protein capable of direct interactions with the channels.

We have recently reported that agonist-induced internalization of calcium channels underlies in part the G protein-mediated inhibition of calcium current. Imaging experiments in living sensory neurons show that, within seconds of receptor activation, calcium channels are cleared from the membrane and sequestered into clathrin-coated vesicles. Disruption of the L1-CAM/ankyrin B complex with the calcium channel by cell-permeant peptides mimics transmitter-induced trafficking of the channels, reduces calcium influx and decreases exocytosis. Our results suggest that G protein-induced removal of plasma membrane calcium channels is a consequence of disrupting channel-cytoskeleton interactions and might represent a novel mechanism of presynaptic inhibition. On-going experiments in our laboratory are studying the molecular mechanisms of G protein-mediated trafficking of calcium channels in neurons and cardiac myocytes.

Lipsky R, Potts EM, Puckerin AA, Stocks J, Tarzami ST, Schecter AD, Sobie EA, Akar FG, Diverse-Pierluissi MA. Beta-adrenergic receptor mediated regulation of cardiac Cav1.2 channel complexes. J Biol Chem 2008 May 5; Epub ahead of print.

Iyengar R, Diverse-Pierluissi MA, Jenkins SL, Chan AM, Devi LA, Sobie EA, Ting AT, Weinstein DC. Inquiry learning. Integrating content detail and critical reasoning by peer review. Science 2008 Feb 29; 319(5867): 1189-1190.

Puckerin A, Liu L, Permaul N, Carman P, Lee J, Diverse-Pierluissi MA. Arrestin is required for agonist-induced trafficking of voltage-dependent calcium channels. J Biol Chem 2006 Oct 13; 281(41): 31131-41.

Tombler E, Cabanilla NJ, Carman P, Hall JJ, Richman R, Rodriguez J, Lee J, Felsenfeld DP, Hennigan RF, Diverse-Pierluissi MA. G protein-induced spatial redistribution of voltage-dependent calcium channels. J Biol Chem 2006; 281: 1827-1839.

Richman RW, Tombler E, Lau KK, Anantharam A, Rodriguez J, O'Bryan JP, Diverse-Pierluissi MA. N type Ca2+ channels as scaffold proteins in the assembly of signaling molecules for GABAB receptor effects. J Biol Chem 2004 Jun 4; 279(23): 24649-24658.

Schiff ML, Siderovski DP, Brothers G, Snow B, Jordan JD, De Vries L, Ortiz DF, Diverse-Pierluissi M. Tyrosine kinase-dependent recruitment of RGS12 to N-type calcium channel. Nature 2000; 408: 723-727.

Diverse-Pierluissi MA, Inglese J, Stoffel RH, Lefkowitz RJ, Dunlap K. G protein-coupled receptor kinase mediates desensitization of norepinephrine-induced calcium current inhibition. Neuron 1996; 16: 579-585.