The long-term goal of this proposal is to understand how neurotransmitters act through G protein-coupled receptors to modulate the activities of neurons. Our studies focus on a neurotransmitter signaling pathway that regulates activities of the neurons and muscles of the egg-laying system of C. elegans. We have identified mutations that disrupt the regulation of egg-laying behavior and used them to identify and study genes encoding components of this G protein signaling pathway. The genes analyzed so far have close homologs expressed in the mammalian brain, suggesting that C. elegans will prove a useful model for understanding neurotransmission through G proteins in humans. The first major aim of this proposal is to systematically exploit the molecular genetic system we have developed to analyze this neurotransmitter signaling pathway. We will carry out saturating genetic screens to identify as many of the signaling genes as possible. We will clone and molecularly analyze these genes. Our goal is to eventually reduce our understanding of this G protein signaling pathway to a biochemical level. The potential of this approach is illustrated by the fact that we have already used it to identify a protein, EGL-10, that inhibits signaling by a heterotrimeric G protein in the C. elegans egg-laying system. EGL-10 is a prototype for a large family of proteins we identified in worms and humans that we have named the """"""""regulator of G protein signaling"""""""" (RGS) proteins. These RGS proteins may regulate may or all G protein signaling pathways. The second major aim of this proposal is to determine why there are so many RGS proteins. Are they simply redundant, or does each have a specific biological function, perhaps because each is restricted to interacting with a particular G protein or set of G proteins? We will examine this issue by determining the genetic functions and expression patterns of the 11 worm RGS proteins and by studying the biochemical specificity of the interactions between C. elegans RGS and G proteins in vitro. this analysis should reveal the logic by which the family of RGS proteins regulates multiple signaling pathways in the worm. Because many C. elegans G proteins and RGS proteins are closely related to corresponding human homologs, our analysis should shed light on analogous human signaling pathways and direct their further study.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036918-02
Application #
2839419
Study Section
Genetics Study Section (GEN)
Program Officer
Leblanc, Gabrielle G
Project Start
1997-12-08
Project End
2001-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Ghosh, D Dipon; Sanders, Tom; Hong, Soonwook et al. (2016) Neural Architecture of Hunger-Dependent Multisensory Decision Making in C. elegans. Neuron 92:1049-1062
Collins, Kevin M; Bode, Addys; Fernandez, Robert W et al. (2016) Activity of the C. elegans egg-laying behavior circuit is controlled by competing activation and feedback inhibition. Elife 5:
Koelle, Michael R (2016) Neurotransmitter signaling through heterotrimeric G proteins: insights from studies in C. elegans. WormBook :1-78
Coleman, Brantley D; Marivin, Arthur; Parag-Sharma, Kshitij et al. (2016) Evolutionary Conservation of a GPCR-Independent Mechanism of Trimeric G Protein Activation. Mol Biol Evol 33:820-37
Kosmaczewski, Sara Guckian; Han, Sung Min; Han, Bingjie et al. (2015) RNA ligation in neurons by RtcB inhibits axon regeneration. Proc Natl Acad Sci U S A 112:8451-6
Han, Bingjie; Bellemer, Andrew; Koelle, Michael R (2015) An evolutionarily conserved switch in response to GABA affects development and behavior of the locomotor circuit of Caenorhabditis elegans. Genetics 199:1159-72
Li, Pengpeng; Collins, Kevin M; Koelle, Michael R et al. (2013) LIN-12/Notch signaling instructs postsynaptic muscle arm development by regulating UNC-40/DCC and MADD-2 in Caenorhabditis elegans. Elife 2:e00378
Collins, Kevin M; Koelle, Michael R (2013) Postsynaptic ERG potassium channels limit muscle excitability to allow distinct egg-laying behavior states in Caenorhabditis elegans. J Neurosci 33:761-75
Gurel, Guliz; Gustafson, Megan A; Pepper, Judy S et al. (2012) Receptors and other signaling proteins required for serotonin control of locomotion in Caenorhabditis elegans. Genetics 192:1359-71
Hofler, Catherine; Koelle, Michael R (2011) AGS-3 alters Caenorhabditis elegans behavior after food deprivation via RIC-8 activation of the neural G protein G ýýo. J Neurosci 31:11553-62

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