G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger

Definition

Target type: biologicalprocess

A G protein-coupled receptor signaling pathway in which the signal is transmitted via the activation or inhibition of a nucleotide cyclase activity and a subsequent change in the concentration of a cyclic nucleotide. [GOC:mah, GOC:signaling, ISBN:0815316194]

G protein-coupled receptor (GPCR) signaling pathways coupled to cyclic nucleotide second messengers represent a fundamental mechanism of cellular communication, playing a crucial role in diverse physiological processes. These pathways involve a series of molecular events initiated by the binding of an extracellular ligand to a GPCR, ultimately leading to the generation of intracellular second messengers, cAMP or cGMP, which modulate downstream signaling cascades.

The process begins with the ligand, such as a hormone, neurotransmitter, or sensory stimulus, interacting with its specific GPCR, triggering a conformational change in the receptor. This conformational change exposes a binding site for a heterotrimeric G protein, composed of alpha, beta, and gamma subunits. The activated GPCR then facilitates the exchange of GDP for GTP on the alpha subunit of the G protein, causing the alpha subunit to dissociate from the beta-gamma dimer.

Depending on the specific GPCR and G protein involved, the activated alpha subunit can either stimulate or inhibit adenylyl cyclase, an enzyme responsible for the synthesis of cAMP. Stimulation of adenylyl cyclase leads to an increase in intracellular cAMP levels, whereas inhibition results in a decrease. Similarly, the activated alpha subunit can also modulate guanylyl cyclase, the enzyme responsible for cGMP synthesis, leading to changes in intracellular cGMP levels.

cAMP and cGMP act as second messengers, relaying the extracellular signal to downstream effectors. In the case of cAMP, the primary effector is protein kinase A (PKA), which is activated by binding to cAMP. Activated PKA then phosphorylates specific target proteins, altering their activity and ultimately triggering a wide range of cellular responses, including changes in gene expression, enzyme activity, and cell morphology.

cGMP, on the other hand, activates protein kinase G (PKG) and cGMP-gated ion channels. PKG phosphorylates various substrates, modulating cellular processes like smooth muscle relaxation, neurotransmission, and cell growth. cGMP-gated ion channels, primarily found in sensory neurons and photoreceptor cells, mediate the influx of ions, leading to changes in membrane potential and downstream signaling events.

The GPCR signaling pathway is tightly regulated through a series of feedback mechanisms. These mechanisms ensure that the signal is transduced efficiently and that the pathway is shut off when the ligand is no longer present. One important mechanism involves the intrinsic GTPase activity of the alpha subunit, which hydrolyzes GTP to GDP, causing the alpha subunit to reassociate with the beta-gamma dimer and inactivate the G protein. Additionally, the GPCR itself can undergo desensitization, a process where it is phosphorylated by specific kinases, reducing its ability to activate G proteins.

GPCR signaling pathways coupled to cyclic nucleotide second messengers are highly versatile and play crucial roles in regulating a wide array of physiological processes. These pathways are involved in sensory perception, neurotransmission, hormone secretion, cardiovascular function, immune responses, and many other essential cellular activities. Understanding the intricacies of these pathways is critical for developing novel therapeutic strategies for a wide range of diseases, including cancer, diabetes, and neurodegenerative disorders.'
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Proteins (49)

Compounds (1,294)