A comparison of agonist‐specific coupling of cloned human α₂‐adrenoceptor subtypes

Abstract

1 The agonist-speci®c coupling properties of the three cloned human a 2 -adrenoceptor subtypes have been compared, when expressed at similar levels in Chinese hamster ovary (CHO) cell lines, using noradrenaline and (+)-meta-octopamine as agonists. 2 Noradrenaline can couple the receptor to both the inhibition and stimulation of forskolinstimulated cyclic AMP production in all three receptor subtypes, with the relative strength of the coupling to the pathways varying for each of the receptor subtypes. 3 meta-Octopamine selectively couples the a 2A -adrenoceptor only to the inhibition of forskolinstimulated cyclic AMP production. However, meta-octopamine couples the a 2B -and a 2C -adrenoceptors to both the inhibition and stimulation of forskolin-stimulated cyclic AMP production. 4 The relative potency of meta-octopamine to noradrenaline varies between the di erent a 2 -adrenoceptor subtypes. The e ects of meta-octopamine are around two orders of magnitude less potent than those of noradrenaline on both the a 2A -and a 2B -adrenoceptor subtypes. In contrast, in the case of the a 2C -adrenoceptor, meta-octopamine is only one order of magnitude less potent than noradrenaline in the stimulation of forskolin-stimulated cyclic AMP production and, in addition, is equipotent with noradrenaline in the inhibition of forskolin-stimulated cyclic AMP production and has an increased maximal response. This raises the possibility that meta-octopamine may have physiologically important actions via a 2C -adrenoceptors in vivo. 5 The results show that the modulation of cyclic AMP production occurs in both a subtype-and agonist-speci®c manner for a 2A -adrenoceptors and in a subtype speci®c manner for a 2B -and a 2C -adrenoceptors.

Detection of G Protein-selective G Protein-coupled Receptor (GPCR) Conformations in Live Cells

“…Metoprolol inhibition of cAMP accumulation was sensitive to PTX treatment, a characteristic of G i stimulation induced by a receptor-ligand combination (Fig. 7c) (36). In contrast, saturating concentrations of ICI 118,551 (10 M) did not alter basal FRET levels for either the ␤2-AR-s-pep or ␤2-AR-i-pep sensors.…”

Review of octopamine in insect nervous systems

“…In contrast, two serine residues are separated by either one or two intervening amino acids in the OCTβ-R and TYR1-R classes ( Figure 6). Such differences in the amino acid chain and in the number of intervening residues may depend on the variation in agonist binding affinity with different receptor subtypes due to coupling capacities with second messenger systems via different G proteins (G s, G i , and G q ) involving different signaling enzymes such as adenylyl cyclase, protein kinase C, and phospholipase C. 160,170 Octopamine and tyraminemediated signaling Similar to other biogenic amines, octopamine and tyramine signaling is mediated through binding to distinct receptors that belong to a family of metabotropic G protein-coupled receptors ( Figure 7). The second messengers include Ca 2+ , cAMP, inositol-1,4,5-trisphosphate, and diacylglycerol, depending on species, tissue source, receptor type, and cell line used for the expression of cloned receptor.…”

“…168,169 These residues are separated by intervening amino acid residues. 170 A multiple sequence alignment of insect octopaminergic and tyraminergic receptor sequences produced by ClustalW (2.0.12) 171 shows that the conserved serine residues in TM5 are separated by a chain of alanine, leucine, and glycine in the Octα-R class. Similar to the OCTα-R class, separation is achieved by three intervening amino acid residues in the TYR2-R class but the leucine residue in the alanineleucine-glycine chain is replaced with methionine ( Figure 6).…”

Cellular and Molecular Mechanisms of Pain Control by Opiates

“…We could do patch clamp analysis of spinal cord neurons to ask if DAMGO and dynorphin vary in their efficacy at stimulating these two pathways. Agonist-specific coupling has been described in the adrenergic system, where noradrenaline and octopamine stimulate alpha-2 adrenergic receptors (Rudling, Richardson et al 2000) to activate different effector pathways, depending on agonist.…”