GPCRs can activate phospholipase A2, an enzyme that releases arachidonic acid from membrane phospholipids. Arachidonic acid can regulate neighboring cells or stimulate inflammation when released from cells. It can also be retained within cells and incorporated into the plasma membrane or metabolized in the cytosol to form intracellular second messengers. Cytosolic cyclooxygenases facilitate the metabolism of arachidonic acid to prostaglandins, thromboxanes, and prostacyclins. Prostaglandins mediate platelet aggregation, cause airway constriction, and induce inflammation. Thromboxanes induce platelet aggregation and constrict blood vessels, while prostacyclin inhibits platelet aggregation and dilates blood vessels. Another pathway involves the conversion of arachidonic acid to leukotrienes by the enzyme 5-lipoxygenase, which participate in allergic and inflammatory responses. The third pathway involves the generation of hydroxyeicosatetraenoic acid (HETE) and cis-epoxyeicosatrienoic acid (cis-EET) by the enzyme epoxygenase. These metabolites increase calcium release from the endoplasmic reticulum, stimulate cell proliferation, and regulate inflammatory responses.

Calcium ions (Ca++) act as intracellular messengers and bind to calcium-binding proteins such as calmodulin (CaM). The binding of Ca++ to CaM induces a conformational change, allowing CaM to regulate other signaling proteins. This includes the regulation of cAMP phosphodiesterase, an enzyme that degrades cAMP to AMP. CaM also phosphorylates specific serine and threonine residues in proteins, including myosin light-chain kinase, which facilitates smooth muscle contraction.

To terminate signals initiated by cAMP and cGMP, phosphodiesterases enhance the degradation of these cyclic nucleotides, while protein phosphatases dephosphorylate effectors. Ligand activation of GPCRs activates phosphodiesterases, facilitating the breakdown of cAMP and cGMP to AMP and GMP, respectively. The balance between kinase-mediated phosphorylation and phosphatase-mediated dephosphorylation allows for rapid regulation of the activity of signaling proteins.

There are various classes of receptors with enzymatic activity or associations with enzymatic proteins. These include receptors that mediate cellular responses to atrial natriuretic peptide (ANP) and nitric oxide (guanylyl cyclase receptors), transforming growth factor-β (TGF-β; threonine/serine kinase receptors), EGF, platelet-derived growth factor (PDGF), and insulin (tyrosine kinase receptors), and interleukins (tyrosine kinase–associated receptors).
Ligand binding to GPCRs can also activate phospholipase A2, an enzyme that releases arachidonic acid from membrane phospholipids Arachidonic acid, which can also be released from diacylglycerol via an indirect pathway, can be released from cells and thereby regulate neighboring cells or stimulate inflammation. It can also be retained within cells, where it is incorporated into the plasma membrane or is metabolized in the cytosol to form intracellular second messengers that affect the activity of enzymes and ion channels. In one pathway, cytosolic cyclooxygenases facilitate the metabolism of arachidonic acid to prostaglandins, thromboxanes, and prostacyclins. Prostaglandins mediate aggregation of platelets, cause constriction of the airways, and induce inflammation. Thromboxanes also induce platelet aggregation and constrict blood vessels, whereas prostacyclin inhibits platelet aggregation and causes dilation of blood vessels. In a second pathway of arachidonic acid metabolism, the enzyme 5-lipoxygenase initiates the conversion of arachidonic acid to leukotrienes, which participate in allergic and inflammatory responses, including those causing asthma, rheumatoid arthritis, and inflammatory bowel disease. The third pathway of arachidonic acid metabolism is initiated by epoxygenase, an enzyme that facilitates the generation of hydroxyeicosatetraenoic acid (HETE) and cis-epoxyeicosatrienoic acid (cis-EET). HETE and cis-EET and their metabolites increase release of Ca++ from the endoplasmic reticulum, stimulate cell proliferation, and regulate inflammatory responses.
Ca++ is also an intracellular messenger that elicits cellular effects via Ca++-binding proteins, most notably calmodulin (CaM). When Ca++ binds to CaM, its conformation is altered, and the structural change in CaM allows it to bind to and regulate other signaling proteins, including cAMP phosphodiesterase, an enzyme that degrades cAMP to AMP, which is inactive and unable to activate PKA. By binding to CaM-dependent kinases, CaM also phosphorylates specific serine and threonine residues in many proteins, including myosin light-chain kinase, which facilitates smooth muscle contraction (see
Protein Phosphatases and Phosphodiesterases Counteract the Activation of Cyclic Nucleotide Kinases
There are two ways to terminate a signal initiated by cAMP and cGMP: enhancing degradation of these cyclic nucleotides by phosphodiesterases and dephosphorylation of effectors by protein phosphatases. Phosphodiesterases facilitate the breakdown of cAMP and cGMP to AMP and GMP, respectively, and are activated by ligand activation of GPCRs. Phosphatases dephosphorylate effector proteins that were phosphorylated by kinases such as PKA. The balance between kinase-mediated phosphorylation and phosphatase-mediated dephosphorylation allows rapid and exquisite regulation of the phosphorylated state and thus the activity of signaling proteins.
There are several classes of receptors that have enzymatic activity or are intimately associated with proteins that have enzymatic activity. Four of these classes are discussed next, including receptors that mediate the cellular responses to atrial natriuretic peptide (ANP) and nitric oxide (guanylyl cyclase receptors); transforming growth factor-β (TGF-β; threonine/serine kinase receptors); EGF, platelet-derived growth factor (PDGF), and insulin (tyrosine kinase receptors); and interleukins (tyrosine kinase–associated receptors).