G protein-coupled receptor kinase mediates desensitization of norepinephrine-induced Ca2+ channel inhibition.
G protein-coupled receptors are essential signaling molecules at sites of synaptic transmission. Here, we explore the mechanisms responsible for the use-dependent termination of metabotropic receptor signaling in embryonic sensory neurons. We report that the inhibition of voltage-dependent Ca2+ channels mediated by alpha2-adrenergic receptors desensitizes slowly with prolonged exposure to the transmitter and that the desensitization is mediated by a G protein-coupled receptor kinase (GRK). Intracellular introduction of recombinant, purified kinases or synthetic blocking peptides into individual neurons demonstrates the specific involvement of a GRK3-like protein. These results suggest that GRK-mediated termination of receptor-G protein coupling is likely to regulate synaptic strength and, as such, may provide one effective mechanism for depression of synaptic transmission.
Diverse-Pierluissi
M
M
Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.
Inglese
J
J
Stoffel
R H
RH
Lefkowitz
R J
RJ
Dunlap
K
K
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D002478:Cells, Cultured; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D011494:Protein Kinases / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000502:physiology
D015220:Calcium Channels; D011494:Protein Kinases; D019204:GTP-Binding Proteins; D009638:Norepinephrine