Abstract
Neurotransmitters signal via G protein coupled receptors (GPCRs) to modulate activity of neurons and muscles. C. elegans has ∼150 G protein coupled neuropeptide receptor homologs and 28 additional GPCRs for small-molecule neurotransmitters. Genetic studies in C. elegans demonstrate that neurotransmitters diffuse far from their release sites to activate GPCRs on distant cells. Individual receptor types are expressed on limited numbers of cells and thus can provide very specific regulation of an individual neural circuit and behavior. G protein coupled neurotransmitter receptors signal principally via the three types of heterotrimeric G proteins defined by the G alpha subunits Gαo, Gαq, and Gαs. Each of these G alpha proteins is found in all neurons plus some muscles. Gαo and Gαq signaling inhibit and activate neurotransmitter release, respectively. Gαs signaling, like Gαq signaling, promotes neurotransmitter release. Many details of the signaling mechanisms downstream of Gαq and Gαs have been delineated and are consistent with those of their mammalian orthologs. The details of the signaling mechanism downstream of Gαo remain a mystery. Forward genetic screens in C. elegans have identified new molecular components of neural G protein signaling mechanisms, including Regulators of G protein Signaling (RGS proteins) that inhibit signaling, a new Gαq effector (the Trio RhoGEF domain), and the RIC-8 protein that is required for neuronal Gα signaling. A model is presented in which G proteins sum up the variety of neuromodulator signals that impinge on a neuron to calculate its appropriate output level.
Highlights
The nervous system functions through the use of neurotransmitters that act as chemical signals between cells
This review focuses on insights into the molecular mechanisms and biological functions of neurotransmitter signaling through G protein coupled receptors (GPCRs) that arise from studies in the model organism C. elegans
An interesting case is that of the dopamine receptor DOP-2, which was assigned to Gαi/o in heterologous cell studies, and for which C. elegans genetics suggests that three different Gαo-related Gα proteins may mediate DOP-2 signaling in worms (Suo et al, 2003; Suo et al, 2009; Correa et al, 2012; Pandey and Harbinder, 2012; Mersha et al 2013)
Summary
The nervous system functions through the use of neurotransmitters that act as chemical signals between cells. GPCRs activate intracellular signaling pathways that can have indirect effects on ion channel activity, and electrophysiological studies in the same model organisms have given important insights into how GPCR signaling modulates the function of neural circuits (Bailey and Kandel, 2008; Marder, 2012). The simplicity of the C. elegans nervous system, combined with the use of genetics, has allowed biological functions to be assigned to signaling by specific neurotransmitters acting through specific GPCRs on individual identified neurons. Enough such biological functions of neural G protein signaling have been described that the long-elusive big-picture understanding of the whole purpose of this mode of neurotransmission is beginning to emerge
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