Voltage-dependent Ca2+ channels have evolved to regulate physiological processes as diverse as gene transcription and muscle contraction. In the central nervous system, several structurally and pharmacologically distinct Ca2+ channel types are co-localized in nerve terminals, and, jointly, they control exocytosis. As the minor biophysical differences among these exocytotic Ca2+ channels are unlikely to provide much variation in excitation-secretion coupling, the biological rationale underlying their co-localization in nerve terminals is unclear. Experiments in this application will explore the hypothesis that each of these channel types is uniquely regulated by biochemical pathways activated by extracellular transmitters. Such differential modulation of the channels might, in part, underlie activity-dependent changes in synaptic strength, such as long-term depression or potentiation. Proposed investigations will focus on two specific Ca2+ channel types--N and P-- each to be separately studied in embryonic chick sensory neurons. Experiments will I) describe the modulatory pathways that control N channels, 2) determine whether P channels are similarly modulated, 3) study activity-dependent variation in modulatory efficacy, and 4) assess the physiological significance of differential modulation at the level of transmitter release. Results will help to sort out the complex network of biochemical pathways that impinge on voltage-dependent Ca2+ channels and offer insight into the organizing principles fundamental to synaptic plasticity and, ultimately, to cognitive processing in the nervous system.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Program Officer
Leblanc, Gabrielle G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tufts University
Schools of Medicine
United States
Zip Code
Erickson, M A; Haburcak, M; Smukler, L et al. (2007) Altered functional expression of Purkinje cell calcium channels precedes motor dysfunction in tottering mice. Neuroscience 150:547-55
Tosetti, Patrizia; Dunlap, Kathleen (2004) Assays of RGS3 activation and modulation. Methods Enzymol 390:99-119
Tosetti, Patrizia; Pathak, Narendra; Jacob, Michele H et al. (2003) RGS3 mediates a calcium-dependent termination of G protein signaling in sensory neurons. Proc Natl Acad Sci U S A 100:7337-42
Tosetti, Patrizia; Parente, Valeria; Taglietti, Vanni et al. (2003) Chick RGS2L demonstrates concentration-dependent selectivity for pertussis toxin-sensitive and -insensitive pathways that inhibit L-type Ca2+ channels. J Physiol 549:157-69
Zhou, Yu Dong; Turner, Timothy J; Dunlap, Kathleen (2003) Enhanced G protein-dependent modulation of excitatory synaptic transmission in the cerebellum of the Ca2+ channel-mutant mouse, tottering. J Physiol 547:497-507
Tosetti, Patrizia; Turner, Timothy; Lu, Qiang et al. (2002) Unique isoform of Galpha -interacting protein (RGS-GAIP) selectively discriminates between two Go-mediated pathways that inhibit Ca2+ channels. J Biol Chem 277:46001-9
Lu, Q; AtKisson, M S; Jarvis, S E et al. (2001) Syntaxin 1A supports voltage-dependent inhibition of alpha1B Ca2+ channels by Gbetagamma in chick sensory neurons. J Neurosci 21:2949-57
Diverse-Pierluissi, M; McIntire, W E; Myung, C S et al. (2000) Selective coupling of G protein beta gamma complexes to inhibition of Ca2+ channels. J Biol Chem 275:28380-5
Ikeda, S R; Dunlap, K (1999) Voltage-dependent modulation of N-type calcium channels: role of G protein subunits. Adv Second Messenger Phosphoprotein Res 33:131-51
Loechner, K J; Knox, R J; McLaughlin, J T et al. (1999) Dexamethasone-mediated inhibition of calcium transients and ACTH release in a pituitary cell line (AtT-20). Steroids 64:404-12

Showing the most recent 10 out of 30 publications