Abstract
Heterotrimeric G proteins regulate a vast array of cellular functions via specific intracellular effectors. Accumulating pharmacological and biochemical studies implicate Gβ subunits as signaling molecules interacting directly with a wide range of effectors to modulate downstream cellular responses, in addition to their role in regulating Gα subunit activities. However, the native biological roles of Gβ-mediated signaling pathways in vivo have been characterized only in a few cases. Here, we identified a Gβ GPB-1 signaling pathway operating in specific serotonergic neurons to the define steady state serotonin (5-HT) synthesis, through a genetic screen for 5-HT synthesis mutants in Caenorhabditis elegans. We found that signaling through cell autonomous GPB-1 to the OCR-2 TRPV channel defines the baseline expression of 5-HT synthesis enzyme tryptophan hydroxylase tph-1 in ADF chemosensory neurons. This Gβ signaling pathway is not essential for establishing the serotonergic cell fates and is mechanistically separated from stress-induced tph-1 upregulation. We identified that ADF-produced 5-HT controls specific innate rhythmic behaviors. These results revealed a Gβ-mediated signaling operating in differentiated cells to specify intrinsic functional properties, and indicate that baseline TPH expression is not a default generic serotonergic fate, but is programmed in a cell-specific manner in the mature nervous system. Cell-specific regulation of TPH expression could be a general principle for tailored steady state 5-HT synthesis in functionally distinct neurons and their regulation of innate behavior.
Highlights
Serotonin (5-HT) is a neuromodulator implicated in stress-triggered behaviors such as aggression, anxiety, as well as in diverse innate behaviors and physiological processes ranging from food intake to rhythmic motor acts and circadian cycles [1]
Gβ Signaling Controls Steady State 5-HT Synthesis canonical heterotrimeric G protein signaling pathways where Gα subunits drive downstream effectors, we found that signaling through Gβ GPB-1 to the OCR-2 TRPV channel defines the baseline tph-1 expression
This Gβ signaling is not required for the establishment or maintenance of the serotonergic cell fates, but dedicated to set steady state 5-HT synthesis in mature neurons
Summary
Serotonin (5-HT) is a neuromodulator implicated in stress-triggered behaviors such as aggression, anxiety, as well as in diverse innate behaviors and physiological processes ranging from food intake to rhythmic motor acts and circadian cycles [1]. While the signaling pathways specifying serotonergic cell fates have been studied extensively, little is known about the genetic program defining 5-HT production in mature nervous systems. It is generally assumed that the baseline 5-HT synthesis is a feature of default serotonergic cell fates [6]. This view, does not address how basal levels of Tph, encoding the CNS 5-HT synthesis rate-limiting enzyme tryptophan hydroxylase, display stereotyped spatiotemporal changes after the 5-HT cell fate established [7]. The genetic programs that define steady state 5-HT synthesis in functionally distinct neurons and its mechanistic relation to stress-induced changes in 5-HT synthesis in an animal remain to be discovered
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