Editing G protein-coupled receptor (section)

===G-protein-dependent signaling===

There are three main G-protein-mediated signaling pathways, mediated by four [[class (biology)|sub-classes]] of G-proteins distinguished from each other by [[sequence homology]] ([[Gαs|G<sub>αs</sub>]], [[Gαi|G<sub>αi/o</sub>]], [[Gαq|G<sub>αq/11</sub>]], and [[G12/G13 alpha subunits|G<sub>α12/13</sub>]]). Each sub-class of G-protein consists of multiple proteins, each the product of multiple [[genes]] or [[splice variant|splice variations]] that may imbue them with differences ranging from subtle to distinct with regard to signaling properties, but in general they appear reasonably grouped into four classes. Because the signal transducing properties of the various possible [[G beta-gamma complex|βγ combinations]] do not appear to radically differ from one another, these classes are defined according to the isoform of their α-subunit.<ref name="Wettschureck_2005"/>{{rp|1163}}

While most GPCRs are capable of activating more than one Gα-subtype, they also show a preference for one subtype over another. When the subtype activated depends on the ligand that is bound to the GPCR, this is called [[functional selectivity]] (also known as agonist-directed trafficking, or conformation-specific agonism). However, the binding of any single particular [[agonist]] may also initiate activation of multiple different G-proteins, as it may be capable of stabilizing more than one conformation of the GPCR's [[guanine nucleotide exchange factor|GEF]] domain, even over the course of a single interaction. In addition, a conformation that preferably activates one [[isoform]] of Gα may activate another if the preferred is less available. Furthermore, [[feedback]] pathways may result in [[post-translational modification|receptor modifications]] (e.g., phosphorylation) that alter the G-protein preference. Regardless of these various nuances, the GPCR's preferred coupling partner is usually defined according to the G-protein most obviously activated by the [[endogenous]] ligand under most [[physiological]] or [[experimental]] conditions.

====Gα signaling====

# The effector of both the G<sub>αs</sub> and G<sub>αi/o</sub> pathways is the [[cyclic amp|cyclic-adenosine monophosphate]] (cAMP)-generating enzyme [[adenylyl cyclase|adenylate cyclase]], or AC. While there are ten different AC gene products in mammals, each with subtle differences in [[tissue (biology)|tissue]] distribution or function, all [[catalyze]] the conversion of [[cytosolic]] [[adenosine triphosphate]] (ATP) to cAMP, and all are directly stimulated by G-proteins of the G<sub>αs</sub> class. In contrast, however, interaction with Gα subunits of the G<sub>αi/o</sub> type inhibits AC from generating cAMP. Thus, a GPCR coupled to G<sub>αs</sub> counteracts the actions of a GPCR coupled to G<sub>αi/o</sub>, and vice versa. The level of cytosolic cAMP may then determine the activity of various [[cyclic nucleotide-gated ion channel|ion channels]] as well as members of the [[Serine/threonine-specific protein kinase|ser/thr-specific]] [[protein kinase A|protein kinase&nbsp;A]] (PKA) family. Thus cAMP is considered a [[second messenger system|second messenger]] and PKA a secondary [[effector (biology)|effector]].
# The effector of the G<sub>αq/11</sub> pathway is [[phospholipase C|phospholipase C-β]] (PLCβ), which catalyzes the cleavage of membrane-bound [[phosphatidylinositol 4,5-bisphosphate]] (PIP2) into the second messengers [[inositol trisphosphate|inositol (1,4,5) trisphosphate]] (IP3) and [[diglyceride|diacylglycerol]] (DAG). IP3 acts on [[inositol trisphosphate receptor|IP3 receptors]] found in the membrane of the [[endoplasmic reticulum]] (ER) to elicit [[Ca2+|Ca<sup>2+</sup>]] release from the ER, while DAG diffuses along the [[plasma membrane]] where it may activate any membrane localized forms of a second ser/thr kinase called [[protein kinase C]] (PKC). Since many isoforms of PKC are also activated by increases in intracellular Ca<sup>2+</sup>, both these pathways can also converge on each other to signal through the same secondary effector. Elevated intracellular Ca<sup>2+</sup> also binds and [[allosterically]] activates proteins called [[calmodulin]]s, which in turn tosolic [[small GTPase]], [[Rho family of GTPases|Rho]]. Once bound to GTP, Rho can then go on to activate various proteins responsible for [[cytoskeleton]] regulation such as [[Rho-associated protein kinase|Rho-kinase]] (ROCK). Most GPCRs that couple to G<sub>α12/13</sub> also couple to other sub-classes, often G<sub>αq/11</sub>.

====Gβγ signaling====

The above descriptions ignore the effects of [[G beta-gamma complex|Gβγ]]–signalling, which can also be important, in particular in the case of activated G<sub>αi/o</sub>-coupled GPCRs. The primary effectors of Gβγ are various ion channels, such as [[G protein-coupled inwardly-rectifying potassium channel|G-protein-regulated inwardly rectifying K<sup>+</sup> channels]] (GIRKs), [[P-type calcium channel|P]]/[[Q-type calcium channel|Q]]- and [[N-type calcium channel|N-]]type [[voltage-dependent calcium channel|voltage-gated Ca<sup>2+</sup> channels]], as well as some isoforms of AC and PLC, along with some [[PI3K|phosphoinositide-3-kinase]] (PI3K) isoforms.