G-Protein receptors are structural protein that assists in the detection of molecules outside the cells and stimulates internal signal transduction lanes, which triggers a cellular reaction (Ruehr, 2003). As such, G-protein receptors have seven transmembrane proteins with a monomeric heptahelical structure, extracellular N terminus, and intracellular C terminus (Friis, 2002). The transmembrane proteins have no integral channels; thus, they operate by coupling to G-proteins and activating the intracellular signaling pathways. According to Ruehr, (2003), G-protein appears a heterotrimeric complex that consists of α, β, and γ subunits. Due to its structural appearance, G-protein triggers a biological reaction by engaging a cascade of actions (Ruehr, 2003). Usually, the response of G-proteins is demonstrated by their slower and long-lasting movements, which are different from ion channels, which engage complex signal transduction.
Ligands that activates G-protein coupled receptor (GPCR) are mostly hormones and neurotransmitters within the cells (Ruehr, 2003). A large section of ligands interacts with amino acid residues in a cleft between helical transmembrane domains in the seven-transmembrane (7TM) region (Ruehr, 2003). Additionally, the interleukin 3 (IL 3) loops of the receptors are vital for the GPCR-Gs-protein interaction. Figure 1 clearly illustrates the interaction of GPCR-Gs-protein interaction.
The GS protein response is a three elements system, receptor, Gs protein, and effectors, which regulate cell response. Normally, when a GPCP is activated by a ligand, the first messenger impacts the alternation of protein conformation, which allows the receptors to behave like a guanine nucleotide exchange factor (GEF) (Ruehr, 2003). After the change, the receptor’s affinity for the Gs protein increase in number triggering to more interaction, which causes a conformation alteration that moves onto the alpha subunit through the protein domain dynamics (Ruehr, 2003). The process triggers the alpha subunit to catalyze the prior bound GDP to GTP. The Gs protein complex later dissociates from the receptors causing the separation of Gα-GTP from Gβγ, which remains in the membrane-bound.
Alpha subunit intermingles with the effector molecule enzyme, adenylate cyclase (AC), which catalyzes the reactions. When adenylate cyclase is activated, it speeds up the conversion of adenosine triphosphate (ATP) into a second messenger, cAMP in the assistance of cofactors Mg2+ and Mn2+ (Ruehr, 2003). Usually, the secondary messenger goes on to phosphorylate protein kinase A (PKA) by binding to its regulatory subunits, which causes a conformation alternation and activations. Additionally, PKA signaling may be affected by cAMP phosphodiesterase, thus affecting cell response.
Additionally, PKA is an essential component in the transduction cascade as it has the capability to impact cell mechanisms by phosphorylating specific enzymes in variable pathways. In most cases, PKA phosphorylates Ca2+ channels opens up, thus activating the contraction of the cells (Friis, 2002). When the process takes place in cells with Gs, the contraction becomes more efficient (Ruehr, 2003). Other major types of Gs-coupled receptors are Adrenergic (β1,2,3), dopamine (D1 family), prostaglandin (PGD2, PGE2) histamine (H2) and 5-HT (5-HT4). Each of the receptors varies on the ways they perform within the cells.
In the cardiovascular system, a positive chronotropic and inotropic impact are produced by β1 adrenergic receptors. Gs cascade induces sequestration of Ca2+from sarcoplasmic reticulum and phosphorylation of L-type calcium channels, causing calcium influx (Ruehr, 2003). Furthermore, PKA stimulates troponin I and myosin binding protein C triggering to the contractile process (Friis, 2002). In most cases, β2 adrenergic receptors regulated the vasculature together with histamine (H2) and prostaglandin (PGD2, PGE2) receptors (Ruehr, 2003). Unlike in cardiac muscles whereby an upturn of PKA leads to relaxation, as the kinase inhibits myosin light chain kinase responsible for the establishment of myosin-actin bridges.
In CNS D1, Gs-linked receptors trigger cAMP accumulation, which takes place in the second messenger. The process activates the dopaminergic neurons, thus regulating their growth and development (Friis, 2002). In skeletal muscles, Gs-coupled adrenergic receptors trigger to contraction by tethering PKA to its fixing proteins (AKAPs), which colocalizes with SR or Ryr receptors, thus allowing calcium influx that makes the ion available for contraction (Ruehr, 2003). Furthermore, skeletal muscle β2 receptors facilitate a metabolic role, activating glycogenolysis by phosphorylating glycogen phosphorylase and hindering gluconeogenesis by phosphorylating glycogen synthase (Ruehr, 2003). 5-HT4 GPCRs, which activate cAMP are located in the GIT (Friis, 2002). PKA in these tissues appears to stimulate neuronal activity and propulsive motility, while H2 receptors located in GIT trigger gastric acid secretion.
Despite Gα being responsible for most activities, Gβγ carries some crucial roles in cells. In particular, Gβγ is responsible for the inactivation of the Gα subunit since it increases Gα’s affinity to GDP (Ruehr, 2003). The process engages some complex, inhibits or activates AC, which affects the production of cAMP. As such, the activities of Gβγ are similar to a negative feedback system.
During the period of causation of the GPCR pathway, GTPase intrinsic enzymatic activities trigger the hydrolysis of GTP to GDP. The mechanism may be catalyzed by RGS proteins and the mentioned Gβγ complex. GDP remains connected to the alpha subunit, while the other three subunits dissociate, which resume at the backs stage for resting (Ruehr, 2003). Resting gives the process an opportunity to prepare for another cycle of signal transduction cascade (Friis, 2002). Usually, the Gs protein illustrates one of the essential pharmacological targets. β-blockers like propranolol or atenolol are great antiarrhythmics and antihypertensives. H2 blockers such as cimetidine are deployed in the treatment of conditions such as ulcers (Ruehr, 2003). Additionally, 5-HT4 agonist, for example, cisapride is deployed on therapy for GIT reflux. Prostaglandin on their own actions on PGE2, PGD2 are used as potent vasodilators in labor.
Friis, U., Jensen, B., Sethi, S., Andreasen, D., Hansen, P. and Skøtt, O., 2002. Control of Renin Secretion From Rat Juxtaglomerular Cells by cAMP-Specific Phosphodiesterases. Circulation Research, 90(9), pp.996-1003.
Ruehr, M., Russell, M., Ferguson, D., Bhat, M., Ma, J., Damron, D., Scott, J. and Bond, M., 2003. Targeting of Protein Kinase A by Muscle A Kinase-anchoring Protein (mAKAP) Regulates Phosphorylation and Function of the Skeletal Muscle Ryanodine Receptor. Journal of Biological Chemistry, 278(27), pp.24831-24836.
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