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Pathway Description
Gq Serotonergic Smooth Muscle Contraction
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Physiological
Created: 2023-09-04
Last Updated: 2023-11-27
Although numerous GPCRs have the ability to couple to more than one heterotrimeric G protein, a given GPCR is typically classified based on the G protein subfamily (e.g., Gs, Gi/o, or Gq/11) it preferentially activates. Signaling via Gq-coupled receptors in smooth muscle is of particular interest due to its prominent role in promoting airway smooth muscle contraction and contraction of the vascular smooth muscle cells in most blood vessels. Serotonin 5-HT2A couples with Gq receptors. An estimated 90% of the serotonin in the human body is stored in enterochromaffin cells located in the gastrointestinal tract. Once activated, serotonin functions to mobilize intestinal contraction and direction via the stimulation of myenteric neurons. Smooth muscle contraction depends on calcium influx. Calcium increases within the smooth muscle cell through different processes. Transmembrane signaling occurs in the classical GPCR-G protein-effector protein paradigm. An agonist-bound receptor undergoes a conformational change that promotes its association with and activation of the heterotrimeric G protein Gq. The extreme C-terminus of the G alpha subunit is the receptor recognition domain and dictates receptor-Gα specificity. Receptor-Gα association promotes the release of GDP from Gα and binding of GTP. The active GTP-bound Gα dissociates from Gβγ and in turn activates an effector molecule. Phospholipase C (PLC) is the principal effector of Gq-mediated signaling. Eleven different isoforms of PLC exist and exhibit distinct patterns of regulation; members of the PLCβ subfamily tend to mediate the actions of activated Gq. Activated PLC hydrolyzes phosphoinositol 4,5-bisphosphate (PIP2) into 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). The net effect of increased IP3 and DAG levels is to increase intracellular Ca2+ through release from internal stores and influx from membrane-bound channels.
Summarily, activation of the 5-HT2A receptor typically leads to Gq protein-mediated signaling, which is more commonly associated with smooth muscle contraction rather than relaxation. When serotonin (5-HT) or other ligands bind to the 5-HT2A receptor, it triggers a cascade of intracellular events through Gq protein activation. The Gq protein activation leads to the activation of phospholipase C (PLC), which in turn cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 induces the release of calcium ions (Ca2+) from intracellular stores, such as the endoplasmic reticulum. Increased intracellular calcium levels can activate contractile machinery in smooth muscle cells, leading to muscle contraction.
References
Gq Serotonergic Smooth Muscle Contraction References
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