Metalloprotease cleavage of the N terminus of the orphan G protein–coupled receptor GPR37L1 reduces its constitutive activity
| Autor: | Johannes Schmidt, Chu Kong Liew, Robert M. Graham, Tony Ngo, Nicole M. Jones, Nadine Mrad, Nicola J. Smith, James L. J. Coleman |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine G protein Immunoblotting Biochemistry Receptors G-Protein-Coupled Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Heterotrimeric G protein GTP-Binding Protein alpha Subunits Gs medicine Disintegrin Animals Humans Amino Acid Sequence Receptor Molecular Biology Peptide sequence Mice Knockout Metalloproteinase Microscopy Confocal Sequence Homology Amino Acid biology Cell Biology Molecular biology Adenosine Mice Inbred C57BL ADAM Proteins HEK293 Cells 030104 developmental biology Proteolysis Metalloproteases biology.protein Female Mutant Proteins Signal transduction 030217 neurology & neurosurgery Signal Transduction medicine.drug |
| Zdroj: | Science Signaling. 9 |
| ISSN: | 1937-9145 1945-0877 |
| DOI: | 10.1126/scisignal.aad1089 |
| Popis: | Little is known about the pharmacology or physiology of GPR37L1, a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor that is abundant in the cerebellum. Mice deficient in this receptor exhibit precocious cerebellar development and hypertension. We showed that GPR37L1 coupled to the G protein Gα(s) when heterologously expressed in cultured cells in the absence of any added ligand, whereas a mutant receptor that lacked the amino terminus was inactive. Conversely, inhibition of ADAMs (a disintegrin and metalloproteases) enhanced receptor activity, indicating that the presence of the amino terminus is necessary for GPR37L1 signaling. Metalloprotease-dependent processing of GPR37L1 was evident in rodent cerebellum, where we detected predominantly the cleaved, inactive form. However, comparison of the accumulation of cAMP (adenosine 3',5'-monophosphate) in response to phosphodiesterase inhibition in cerebellar slice preparations from wild-type and GPR37L1-null mice showed that some constitutive signaling remained in the wild-type mice. In reporter assays of Gα(s) or Gα(i) signaling, the synthetic, prosaposin-derived peptide prosaptide (TX14A) did not increase GPR37L1 activity. Our data indicate that GPR37L1 may be a constitutively active receptor, or perhaps its ligand is present under the conditions that we used for analysis, and that the activity of this receptor is instead controlled by signals that regulate metalloprotease activity in the tissue. |
| Databáze: | OpenAIRE |
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