Editors' ChoiceReceptors

Trafficking Rapid Responses

Sci. Signal.  02 Aug 2011:
Vol. 4, Issue 184, pp. ec214
DOI: 10.1126/scisignal.4184ec214

Dopamine, a major central nervous system neurotransmitter, activates a family of G protein–coupled receptors, and the D1 subfamily is coupled to adenylyl cyclase through Gαs or Gαolf to stimulate the production of the second messenger adenosine 3′,5′-monophosphate (cAMP). Dopaminergic pathways are implicated in several neurological disorders, including Parkinson’s disease, schizophrenia, and addiction. Although ligand-stimulated receptor endocytosis is often a mechanism for desensitizing cells, Kotowski et al. provide evidence using live-cell imaging techniques and fluorescent biosensors to show that endocytosis promoted the rapid D1 dopamine receptor–mediated increase in cAMP. Tagged versions of the D1 receptor were introduced into either human embryonic kidney (HEK) 293 cells or cultured striatal neurons, and ligand-induced endocytosis over the course of 50 to 250 seconds was quantified; in separate experiments, the production of cAMP over the same time course was measured. Treatments that inhibited clathrin-mediated endocytosis reduced the production of cAMP in response to D1 agonists. In striatal slice preparations, inhibition of clathrin-mediated endocytosis with the chemical inhibitor dynasore blocked the increase in neuronal activity (action potential frequency) in response to a D1-selective agonist. Confocal microscopy of striatal neurons exposed to a D1-selective agonist and expressing tagged D1 suggested that the internalized receptors colocalized with its cognate Gα subunit and with adenylyl cyclase. Thus, for D1 receptors, internalization appears to serve a positive function in the rapid response to ligand stimulation.

S. J. Kotowski, F. W. Hopf, T. Seif, A. Bonci, M. von Zastrow, Endocytosis promotes rapid dopaminergic signaling. Neuron 71, 278–290 (2011). [PubMed]

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