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G Protein‐Coupled Receptors and the G Protein Family
Alfredo Ulloa‐Aguirre, P. Michael Conn
1 Structure of G Protein‐Coupled Receptors
1.1 General Features
1.2 Ligand‐Binding Domain
1.3 G Protein‐Coupling Domain
2 The Heterotrimeric G‐Protein Family
2.2 G Protein‐Regulatory Cycle
2.3 Structural and Functional Relationships of Gα‐Subunit
2.4 Gβγ Structure and Function
3 Regulatory Mechanisms
3.1 Mechanisms that Regulate Receptor Function
3.2 G Protein‐Mediated Regulatory Mechanisms
Putative membrane topography of G protein‐coupled receptors (GPCRs). A: Proposed seven‐transmembrane‐spanning domains of a prototypic GPCR belonging to the rhodopsin/β‐adrenergic family, showing some structural characteristics, including putative glycosylation sites (branched‐like structures) as well as some aminoacid residues involved in signal transduction, receptor phosphorylation, sequestration, and palmitoylation. The structure also shows the location of some spontaneously occurring mutations leading to constitutive activation of the receptor (for example, thyrotropin, melanocyte‐stimulating hormone, luteinizing hormone, rhodopsin, and adrenergic receptors) 250, 263, 281, 370, 398, 409, 427, 492. A region in the NH2‐terminal end of the first intracellular loop (li) involved in effector activation by the human calcitonin receptor also is shown 355. Inset: Proposed arrangement for the transmembrane helices of the β2‐adrenergic receptor, depicting the binding site for epinephrine. Note the proximity between helices 2 and 7, which is characteristic of this family of GPCRs. B, C, D: Putative membrane topographies of the rat gonadotropin‐releasing hormone receptor 232, the β‐adrenergic receptor 363, and the luteinizing hormone/choriogonadotropin receptor 421, respectively, showing some particular structure‐function relationships (11, 542, 21, 33, 153, 175, 176, 193, 405, 420, 421, 473, 545, 538,539,540). PKA, protein kinase A; PKC, protein kinase C.
[Reproduced from Ostrowski et al. 363 with permission].
Pharmacophore map of the catecholamine‐binding site of the β‐adrenergic receptor. A catecholamine ligand is shown in a hypothetical binding site intercalated among the transmembrane helices of the receptor. Each of the large semicircles represents a transmembrane helix of the receptor, inscribed with the type of binding interaction expected. Other G protein‐coupled receptors expected to have similar interactions with their specific ligands are designated in boxes next to each helix. αAR, α‐adrenergic receptor; βAR, β‐adrenergic receptor; DAR, dopaminergic receptor; MAR, muscarinic acetylcholine receptor; 5HT‐R, 5‐hydroxytryptamine (serotonin) receptor. Inset: Model for the ligandbinding site of the β‐adrenergic receptor showing key interactions with the agonist isoproterenol.
[Reproduced from Strader et al. 450, 454 with permission.]
Sequence relationships between mammalian Gα‐subunits and family groupings.
[Reproduced from Hepler and Gilman 184 and Simon et al. 430 with permission.]
Basic regulatory cycle of a G protein involving both GTP‐induced activation and subunit dissociation and GTPase‐dependent inactivation and subunit reassociation. The unoccupied receptor (Ri) interacts with a specific agonist (A), leading to activation of the receptor (Ra), which interacts with the trimeric Gαβγ protein complex, promoting Mg2+ ‐dependent GDP→GTP exchange and subunit dissociation, allowing their interaction with effectors (Ei). GAPs, GTPase‐activating proteins; ℗, phosphorylated receptor; Ea, activated effector.
Crystal structure of Gαt‐GDP. Secondary structure labels for the GTPase domain were derived from the numerical designations used to describe the homologous ras p21 domains. Additional unique helices in Gαt, are labeled A‐G. Locations of inserts, linkers, and switch regions also are labeled 354.
[Reproduced from Rens‐Domiano and Hamm 399 with permission.]
Ras‐dependent (right) and ‐independent (left) pathways of mitogen‐activated protein kinase (MAPK) activation by G protein‐coupled receptors [for example, α1B‐adrenergic receptor (α1B AR) and muscarinic M1‐acetylcholine receptor (M1AChR)] coupled to pertussis toxin‐insensitive (Gαq) G proteins. Gαq activates phospholipase Cβ1 (PLCβ1), resulting in the conversion of phosphatidylinositol‐4,5‐biphosphate to inositol‐1,4,5‐triphosphate (IP3) and diacylglycerol (DAG), which in turn contributes to the activation of protein kinase C (PKC), which then activates Raf kinase by a still poorly understood mechanism. Activated Gαq also interacts with other intracellular signaling molecules [PKC, protein tyrosine kinases (PTK), etc.] to activate the Ras‐regulated MAPK cascade. MEK, mitogen‐activated/extracellular signal‐regulated kinase.
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Article Title: G Protein‐Coupled Receptors and the G Protein Family
Alfredo Ulloa‐Aguirre, P. Michael Conn. G Protein‐Coupled Receptors and the G Protein Family. Compr Physiol 2011, Supplement 20: Handbook of Physiology, The Endocrine System, Cellular Endocrinology: 87-124. First published in print 1998. doi: 10.1002/cphy.cp070106