Receptor recruitment: A mechanism for interactions between G protein-coupled receptors

Abstract

There is a great deal of evidence for synergistic interactions between G protein-coupled signal transduction pathways in various tissues. As two specific examples, the potent effects of the biogenic amines norepinephrine and dopamine on sodium transporters and natriuresis can be modulated by neuropeptide Y and atrial natriuretic peptide, respectively. Here, we report, using a renal epithelial cell line, that both types of modulation involve recruitment of receptors from the interior of the cell to the plasma membrane. The results indicate that recruitment of G protein-coupled receptors may be a ubiquitous mechanism for receptor sensitization and may play a role in the modulation of signal transduction comparable to that of the well established phenomenon of receptor endocytosis and desensitization.There are many examples documenting that the cellular response to catecholamines and other small molecules can be enhanced by peptide hormones. In the nervous system, the efficacy of synaptic transmission is modulated both by peptide neurotransmitters and by biogenic amines (1, 2). In the kidney, the potent effects of the biogenic amines norepinephrine and dopamine (DA) on sodium transporters and natriuresis can be modulated by neuropeptide Y (NPY; refs. 3 and 4) and atrial natriuretic peptide (ANP; refs. 5-8), respectively. Little is known about the molecular basis for such heterologous sensitization. Here, we report that one cellular mechanism by which peptide hormones induce heterologous sensitization involves recruitment of catecholamine receptors from the interior of the cell to the plasma membrane. We show by the use of confocal microscopy and subcellular fractionation that the well established ability of ANP to potentiate the effects of DA and the ability of NPY to potentiate the effects of norepinephrine are attributable to recruitment of these two classes of receptors to the plasma membrane. MATERIALS AND METHODS Na؉ ,K ؉ -ATPase Activity in Single Proximal Tubular Segments. Renal proximal tubular segments were microdissected from a collagenase-treated rat kidney. Individual segments were incubated with the indicated drugs for 30 min at room temperature. Na ϩ ,K ϩ -ATPase activity was measured in single segments by ouabain-sensitive ATP hydrolysis (9). Assays were performed in the presence of 70 mM Na ϩ (V max conditions). This method permits direct measurements of Na ϩ ,K ϩ -ATPase activity in intact permeable cells, wherein effects of changes in Na ϩ influx are eliminated. Results were calculated relative to the length of the tubular segments.Antibodies. Na ϩ ,K ϩ -ATPase, a plasma membrane marker enzyme, was probed with a monoclonal antibody (a kind gift from M. Caplan, Yale University, New Haven, CT). D1 DA receptors were probed with affinity-purified rabbit anti-D1 rat DA receptor antibodies, which recognize the third extracellular loop of the receptor (a kind gift from R. M. Carey, University of Virginia, Charlottesville, VA; ref. 10). ␣ 1A -Adrenergic receptors were probed with affinity-purified...

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Rapid hormonal regulation of N-acetylglucosamine transferase I

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An escort for GPCRs: implications for regulation of receptor density at the cell surface

“…The Similarly, regulated pools of intracellular dopamine D1 receptors exist in tubular renal cells. In these cells, receptor recruitment from cytosolic stores to the plasma membrane is elicited by agonist activation of cell surface receptors 37 or via atrial natriuretic peptidedependent heterologous activation 38 . An analogous phenomenon was also reported for α 1A -adrenoceptors in response to neuropeptide Y stimulation 38 , leading to the concept that receptor recruitment to the plasma membrane might be a mechanism for receptor sensitization.…”

“…In these cells, receptor recruitment from cytosolic stores to the plasma membrane is elicited by agonist activation of cell surface receptors 37 or via atrial natriuretic peptidedependent heterologous activation 38 . An analogous phenomenon was also reported for α 1A -adrenoceptors in response to neuropeptide Y stimulation 38 , leading to the concept that receptor recruitment to the plasma membrane might be a mechanism for receptor sensitization. Selective up-regulation of D1 receptor was subsequently reported in neuronal dendritic spines upon NMDA receptor activation and increased intracellular calcium 39 .…”