Editing G protein-coupled receptor (section)

===G-protein-independent signaling===

Although they are classically thought of working only together, GPCRs may signal through G-protein-independent mechanisms, and heterotrimeric G-proteins may play functional roles independent of GPCRs. GPCRs may signal independently through many proteins already mentioned for their roles in G-protein-dependent signaling such as [[arrestin|β-arrs]], [[G protein-coupled receptor kinase|GRKs]], and [[Src (gene)|Srcs]]. Such signaling has been shown to be physiologically relevant, for example, [[arrestin|β-arrestin]] signaling mediated by the chemokine receptor [[CXCR3]] was necessary for full efficacy chemotaxis of activated T cells.<ref>{{cite journal | vauthors = Smith JS, Nicholson LT, Suwanpradid J, Glenn RA, Knape NM, Alagesan P, Gundry JN, Wehrman TS, Atwater AR, Gunn MD, MacLeod AS, Rajagopal S | title = Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation | journal = Science Signaling | volume = 11 | issue = 555 | pages = eaaq1075 | date = November 2018 | pmid = 30401786 | pmc = 6329291 | doi = 10.1126/scisignal.aaq1075 }}</ref> In addition, further scaffolding proteins involved in [[subcellular localization]] of GPCRs (e.g., [[PDZ (biology)|PDZ-domain]]-containing proteins) may also act as signal transducers. Most often the effector is a member of the [[MAPK]] family.

====Examples====

In the late 1990s, evidence began accumulating to suggest that some GPCRs are able to signal without G proteins. The [[MAPK1|ERK2]] mitogen-activated protein kinase, a key signal transduction mediator downstream of receptor activation in many pathways, has been shown to be activated in response to cAMP-mediated receptor activation in the [[slime mold]] [[Dictyostelium discoideum|''D. discoideum'']] despite the absence of the associated G protein α- and β-subunits.<ref>{{cite journal | vauthors = Kim JY, Haastert PV, Devreotes PN | title = Social senses: G-protein-coupled receptor signaling pathways in Dictyostelium discoideum | journal = Chemistry & Biology | volume = 3 | issue = 4 | pages = 239–43 | date = April 1996 | pmid = 8807851 | doi = 10.1016/S1074-5521(96)90103-9 | doi-access = free }}</ref>

In mammalian cells, the much-studied β<sub>2</sub>-adrenoceptor has been demonstrated to activate the ERK2 pathway after arrestin-mediated uncoupling of G-protein-mediated signaling. Therefore, it seems likely that some mechanisms previously believed related purely to receptor desensitisation are actually examples of receptors switching their signaling pathway, rather than simply being switched off.

In kidney cells, the [[bradykinin receptor B2]] has been shown to interact directly with a protein tyrosine phosphatase. The presence of a tyrosine-phosphorylated [[immunoreceptor tyrosine-based inhibitory motif|ITIM]] (immunoreceptor tyrosine-based inhibitory motif) sequence in the B2 receptor is necessary to mediate this interaction and subsequently the antiproliferative effect of bradykinin.<ref>{{cite journal | vauthors = Duchene J, Schanstra JP, Pecher C, Pizard A, Susini C, Esteve JP, Bascands JL, Girolami JP | title = A novel protein-protein interaction between a G protein-coupled receptor and the phosphatase SHP-2 is involved in bradykinin-induced inhibition of cell proliferation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 43 | pages = 40375–83 | date = October 2002 | pmid = 12177051 | doi = 10.1074/jbc.M202744200 | doi-access = free }}</ref>

====GPCR-independent signaling by heterotrimeric G-proteins====

Although it is a relatively immature area of research, it appears that heterotrimeric G-proteins may also take part in non-GPCR signaling. There is evidence for roles as signal transducers in nearly all other types of receptor-mediated signaling, including [[integrins]], [[receptor tyrosine kinases]] (RTKs), [[cytokine receptors]] ([[JAK-STAT signaling pathway|JAK/STATs]]), as well as modulation of various other "accessory" proteins such as [[guanine nucleotide exchange factor|GEFs]], [[guanosine nucleotide dissociation inhibitors|guanine-nucleotide dissociation inhibitors]] (GDIs) and [[protein phosphatases]]. There may even be specific proteins of these classes whose primary function is as part of GPCR-independent pathways, termed activators of G-protein signalling (AGS). Both the ubiquity of these interactions and the importance of Gα vs. Gβγ subunits to these processes are still unclear.