Mechanism G protein–coupled receptor

1 mechanism

1.1 ligand binding
1.2 conformational change
1.3 g-protein activation/deactivation cycle
1.4 crosstalk

mechanism

cartoon depicting basic concept of gpcr conformational activation. ligand binding disrupts ionic lock between e/dry motif of tm-3 , acidic residues of tm-6. result, gpcr reorganizes allow activation of g-alpha proteins. side perspective view above , side of gpcr set in plasma membrane (the membrane lipids have been omitted clarity). intracellular perspective shows view looking @ plasma membrane inside cell.

the g protein–coupled receptor activated external signal in form of ligand or other signal mediator. creates conformational change in receptor, causing activation of g protein. further effect depends on type of g protein. g proteins subsequently inactivated gtpase activating proteins, known rgs proteins.

ligand binding

gpcrs include: receptors sensory signal mediators (e.g., light , olfactory stimulatory molecules); adenosine, bombesin, bradykinin, endothelin, γ-aminobutyric acid (gaba), hepatocyte growth factor (hgf), melanocortins, neuropeptide y, opioid peptides, opsins, somatostatin, gh, tachykinins, members of vasoactive intestinal peptide family, , vasopressin; biogenic amines (e.g., dopamine, epinephrine, norepinephrine, histamine, glutamate (metabotropic effect), glucagon, acetylcholine (muscarinic effect), , serotonin); chemokines; lipid mediators of inflammation (e.g., prostaglandins, prostanoids, platelet-activating factor, , leukotrienes); , peptide hormones (e.g., calcitonin, c5a anaphylatoxin, follicle-stimulating hormone (fsh), gonadotropin-releasing hormone (gnrh), neurokinin, thyrotropin-releasing hormone (trh), cannabinoids, , oxytocin). gpcrs act receptors stimuli have not yet been identified known orphan receptors.

however, in other types of receptors have been studied, wherein ligands bind externally membrane, ligands of gpcrs typically bind within transmembrane domain. however, protease-activated receptors activated cleavage of part of extracellular domain.

conformational change

crystal structure of activated beta-2 adrenergic receptor in complex gs(pdb entry 3sn6). receptor colored red, gα green, gβ cyan, , gγ yellow. c-terminus of gα located in cavity created outward movement of cytoplasmic parts of tm5 , 6.

the transduction of signal through membrane receptor not understood. known in inactive state, gpcr bound heterotrimeric g protein complex. binding of agonist gpcr results in conformational change in receptor transmitted bound gα subunit of heterotrimeric g protein via protein domain dynamics. activated gα subunit exchanges gtp in place of gdp in turn triggers dissociation of gα subunit gβγ dimer , receptor. dissociated gα , gβγ subunits interact other intracellular proteins continue signal transduction cascade while freed gpcr able rebind heterotrimeric g protein form new complex ready initiate round of signal transduction.

it believed receptor molecule exists in conformational equilibrium between active , inactive biophysical states. binding of ligands receptor may shift equilibrium toward active receptor states. 3 types of ligands exist: agonists ligands shift equilibrium in favour of active states; inverse agonists ligands shift equilibrium in favour of inactive states; , neutral antagonists ligands not affect equilibrium. not yet known how active , inactive states differ each other.

g-protein activation/deactivation cycle

cartoon depicting heterotrimeric g-protein activation/deactivation cycle in context of gpcr signaling

when receptor inactive, gef domain may bound inactive α-subunit of heterotrimeric g-protein. these g-proteins trimer of α, β, , γ subunits (known gα, gβ, , gγ, respectively) rendered inactive when reversibly bound guanosine diphosphate (gdp) (or, alternatively, no guanine nucleotide) active when bound guanosine triphosphate (gtp). upon receptor activation, gef domain, in turn, allosterically activates g-protein facilitating exchange of molecule of gdp gtp @ g-protein s α-subunit. cell maintains 10:1 ratio of cytosolic gtp:gdp exchange gtp ensured. @ point, subunits of g-protein dissociate receptor, each other, yield gα-gtp monomer , tightly interacting gβγ dimer, free modulate activity of other intracellular proteins. extent may diffuse, however, limited due palmitoylation of gα , presence of isoprenoid moiety has been covalently added c-termini of gγ.

because gα has slow gtp→gdp hydrolysis capability, inactive form of α-subunit (gα-gdp) regenerated, allowing reassociation gβγ dimer form resting g-protein, can again bind gpcr , await activation. rate of gtp hydrolysis accelerated due actions of family of allosteric modulating proteins called regulators of g-protein signaling, or rgs proteins, type of gtpase-activating protein, or gap. in fact, many of primary effector proteins (e.g., adenylate cyclases) become activated/inactivated upon interaction gα-gtp have gap activity. thus, @ stage in process, gpcr-initiated signaling has capacity self-termination.

crosstalk

proposed downstream interactions between integrin signaling , gpcrs. integrins shown elevating ca , phosphorylating fak, weakening gpcr signaling.

gpcrs downstream signals have been shown possibly interact integrin signals, such fak. integrin signaling phosphorylate fak, can decrease gpcr gαs activity.