Signaling G protein–coupled receptor

1 signaling

1.1 g-protein-dependent signaling

1.1.1 gα signaling
1.1.2 gβγ signaling


1.2 g-protein-independent signaling

1.2.1 examples
1.2.2 gpcr-independent signaling heterotrimeric g-proteins

signaling

g-protein-coupled receptor mechanism

if receptor in active state encounters g protein, may activate it. evidence suggests receptors , g proteins pre-coupled. example, binding of g proteins receptors affects receptor s affinity ligands. activated g proteins bound gtp.

further signal transduction depends on type of g protein. enzyme adenylate cyclase example of cellular protein can regulated g protein, in case g protein gs. adenylate cyclase activity activated when binds subunit of activated g protein. activation of adenylate cyclase ends when g protein returns gdp-bound state.

adenylate cyclases (of 9 membrane-bound , 1 cytosolic forms known in humans) may activated or inhibited in other ways (e.g., ca2+/calmodulin binding), can modify activity of these enzymes in additive or synergistic fashion along g proteins.

the signaling pathways activated through gpcr limited primary sequence , tertiary structure of gpcr determined particular conformation stabilized particular ligand, availability of transducer molecules. currently, gpcrs considered utilize 2 primary types of transducers: g-proteins , β-arrestins. because β-arr s have high affinity phosphorylated form of gpcrs (see above or below), majority of signaling dependent upon g-protein activation. however, possibility interaction allow g-protein-independent signaling occur.

g-protein-dependent signaling

there 3 main g-protein-mediated signaling pathways, mediated 4 sub-classes of g-proteins distinguished each other sequence homology (gαs, gαi/o, gαq/11, , gα12/13). each sub-class of g-protein consists of multiple proteins, each product of multiple genes or splice variations may imbue them differences ranging subtle distinct regard signaling properties, in general appear reasonably grouped 4 classes. because signal transducing properties of various possible βγ combinations not appear radically differ 1 another, these classes defined according isoform of α-subunit.

while gpcrs capable of activating more 1 gα-subtype, show preference 1 subtype on another. when subtype activated depends on ligand bound gpcr, called functional selectivity (also known agonist-directed trafficking, or conformation-specific agonism). however, binding of single particular agonist may initiate activation of multiple different g-proteins, may capable of stabilizing more 1 conformation of gpcr s gef domain, on course of single interaction. in addition, conformation preferably activates 1 isoform of gα may activate if preferred less available. furthermore, feedback pathways may result in receptor modifications (e.g., phosphorylation) alter g-protein preference. regardless of these various nuances, gpcr s preferred coupling partner defined according g-protein activated endogenous ligand under physiological or experimental conditions.

gα signaling

gβγ signaling

the above descriptions ignore effects of gβγ–signalling, can important, in particular in case of activated gαi/o-coupled gpcrs. primary effectors of gβγ various ion channels, such g-protein-regulated inwardly rectifying k channels (girks), p/q- , n-type voltage-gated ca channels, isoforms of ac , plc, along phosphoinositide-3-kinase (pi3k) isoforms.

g-protein-independent signaling

although classically thought of working together, gpcrs may signal through g-protein-independent mechanisms, , heterotrimeric g-proteins may play functional roles independent of gpcrs. gpcrs may signal independently through many proteins mentioned roles in g-protein-dependent signaling such β-arrs, grks, , srcs. in addition, further scaffolding proteins involved in subcellular localization of gpcrs (e.g., pdz-domain-containing proteins) may act signal transducers. effector member of mapk family.

examples

in late 1990s, evidence began accumulating suggest gpcrs able signal without g proteins. erk2 mitogen-activated protein kinase, key signal transduction mediator downstream of receptor activation in many pathways, has been shown activated in response camp-mediated receptor activation in slime mold d. discoideum despite absence of associated g protein α- , β-subunits.

in mammalian cells, much-studied β2-adrenoceptor has been demonstrated activate erk2 pathway after arrestin-mediated uncoupling of g-protein-mediated signaling. therefore, seems mechanisms believed related purely receptor desensitisation examples of receptors switching signaling pathway, rather being switched off.

in kidney cells, bradykinin receptor b2 has been shown interact directly protein tyrosine phosphatase. presence of tyrosine-phosphorylated itim (immunoreceptor tyrosine-based inhibitory motif) sequence in b2 receptor necessary mediate interaction , subsequently antiproliferative effect of bradykinin.

gpcr-independent signaling heterotrimeric g-proteins

although relatively immature area of research, appears heterotrimeric g-proteins may take part in non-gpcr signaling. there evidence roles signal transducers in other types of receptor-mediated signaling, including integrins, receptor tyrosine kinases (rtks), cytokine receptors (jak/stats), modulation of various other accessory proteins such gefs, guanine-nucleotide dissociation inhibitors (gdis) , protein phosphatases. there may specific proteins of these classes primary function part of gpcr-independent pathways, termed activators of g-protein signalling (ags). both ubiquity of these interactions , importance of gα vs. gβγ subunits these processes still unclear.