We seek to understand how neurotransmitters signal through heterotrimeric G proteins to modulate the activities of neurons. We will focus on the mechanism of signaling by serotonin, defects in which are thought to underlie major depression in humans. Our goal is to understand how the many G protein coupled serotonin receptors function together to mediate appropriate responses to this neurotransmitter, and to find out what happens downstream of receptor activation. C. elegans uses serotonin as a neurotransmitter, and we will use this model system to investigate the mechanism of three different serotonin signaling events. In our first aim, we will characterize a signaling complex that mediates serotonin signaling onto the C. elegans egg-laying muscles. We will test a model in which multiple serotonin receptors and an ERG potassium channel are co-localized to postsynaptic structures so that localized signals produced by serotonin receptor signaling can inhibit the ERG channel to promote muscle contraction. In the second aim, we will study the mechanism by which serotonin released onto the egg-laying muscles also signals back onto the neurons that release it via autoreceptors to feedback inhibit further serotonin release. We will use a combination of genetic and biochemical studies to analyze two new types of signaling regulators that our preliminary results show enhance such feedback signaling: a GPR/GoLoco protein which binds G1 subunits, and the RIC-8 protein which acts as a G protein nucleotide exchange factor. In the third aim, we will study the mechanism by which serotonin signals to slow down C. elegans locomotion behavior. We have used a genetic screen to identify genes required for this serotonin signaling event. We found that two different serotonin receptors are each required for the effect of serotonin on locomotion: knocking out either receptor alone or both together leads to the same strong defect in serotonin response. We will study how these two different serotonin receptors work together. We will also comprehensively analyze a new protein identified by our screen that is required specifically for serotonin signaling, but that is not similar to any protein previously known to be involved in serotonin signaling. The mechanisms of serotonin signaling are highly conserved between C. elegans and humans and the insights made possible by the power of the C. elegans model system should shed light on new details of human serotonin signaling. This will ultimately help to understand the causes of depression and the interventions that can be used to treat it.

Public Health Relevance

This proposal investigates the basic mechanisms by which neurons in the brain communicate with each other using chemical neurotransmitters, focusing in particular on the neurotransmitter serotonin. Defects in signaling by serotonin and other neurotransmitters appear to underlie depression, schizophrenia and other disorders of mental health, but the precise details of these defects are in most cases unknown. Understanding in detail how neurotransmitters act should make it possible to precisely define the defects that cause mental disorders and to thus develop effective treatments for them.)

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS036918-17
Application #
8584328
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Whittemore, Vicky R
Project Start
1997-12-08
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
17
Fiscal Year
2014
Total Cost
$414,867
Indirect Cost
$164,585
Name
Yale University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
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
Bellemer, Andrew; Hirata, Taku; Romero, Michael F et al. (2011) Two types of chloride transporters are required for GABA(A) receptor-mediated inhibition in C. elegans. EMBO J 30:1852-63
Porter, Morwenna Y; Koelle, Michael R (2010) RSBP-1 is a membrane-targeting subunit required by the Galpha(q)-specific but not the Galpha(o)-specific R7 regulator of G protein signaling in Caenorhabditis elegans. Mol Biol Cell 21:232-43
Porter, Morwenna Y; Xie, Keqiang; Pozharski, Edwin et al. (2010) A conserved protein interaction interface on the type 5 G protein beta subunit controls proteolytic stability and activity of R7 family regulator of G protein signaling proteins. J Biol Chem 285:41100-12
Tanis, Jessica E; Bellemer, Andrew; Moresco, James J et al. (2009) The potassium chloride cotransporter KCC-2 coordinates development of inhibitory neurotransmission and synapse structure in Caenorhabditis elegans. J Neurosci 29:9943-54
Tanis, Jessica E; Moresco, James J; Lindquist, Robert A et al. (2008) Regulation of serotonin biosynthesis by the G proteins Galphao and Galphaq controls serotonin signaling in Caenorhabditis elegans. Genetics 178:157-69
Ferkey, Denise M; Hyde, Rhonda; Haspel, Gal et al. (2007) C. elegans G protein regulator RGS-3 controls sensitivity to sensory stimuli. Neuron 53:39-52
Chase, Daniel L; Koelle, Michael R (2007) Biogenic amine neurotransmitters in C. elegans. WormBook :1-15

Showing the most recent 10 out of 15 publications