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Pathway Description
Gi Serotonergic Smooth Muscle Relaxation
Homo sapiens
Category:
Metabolite Pathway
Sub-Category:
Physiological
Created: 2023-09-06
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. Activation of the 5-HT1A receptor typically leads to Gi protein-mediated signaling, which is commonly associated with smooth muscle relaxation rather than contraction. When serotonin (5-HT) or other ligands bind to the 5-HT1A receptor, it triggers a cascade of intracellular events through Gi protein activation. The Gi protein inhibits the activity of adenylate cyclase, which reduces the production of cyclic adenosine monophosphate (cAMP). Reduced cAMP levels can lead to the deactivation of protein kinase A (PKA) and the inhibition of various downstream signaling pathways. In the context of smooth muscle, this reduction in cAMP levels generally leads to smooth muscle relaxation. The physiological effects of serotonin can vary depending on the specific receptors involved, the tissues in question, and the overall context of the signaling pathways. Different serotonin receptors can have opposing effects on smooth muscle, leading to either contraction or relaxation, depending on the receptor subtype and downstream signaling pathways involved. Serotonin increases the motility of the GI tract muscles, induces muscle constriction in the lungs and uterus, influences vessel muscles in both directions (constriction/relaxation), takes part in platelet aggregation, excites nociceptive pain neurons, and influences CNS neurons. Serotonin also plays a role in the symptoms of GI inflammation, acting through different mechanisms to exert pro- or anti-inflammatory activity.
Summarily, Gi inhibits adenylate cyclase 5 which results in the reduced conversion of ATP to cAMP and reduced activation of Protein Kinase A (PKA). Lower PKA activity leads to decreased phosphorylation of certain proteins, including myosin light chain (MLC), in smooth muscle cells. Reduced MLC phosphorylation promotes the activation of myosin light chain kinase (MLCK). Activated PKA can phosphorylate calcium activated potassium channels causing potassium efflux and promoting hyperpolarization. Low potassium levels, and the resulting hyperpolarization, can affect the activity of voltage-gated calcium channels. These channels are involved in calcium influx, which can, in turn, influence cAMP levels and PKA activity. Calcium ions can activate adenylate cyclase, leading to increased cAMP production and PKA activation.
References
Gi Serotonergic Smooth Muscle Relaxation References
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