title: RETRACTED: Metalloprotease cleavage of the N terminus of the orphan G protein-coupled receptor GPR37L1 reduces its constitutive activity.
abstract: 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.
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales 2010, Australia.
authors.forename: James L J
authors.initials: JL
authors.lastname: Coleman
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Ngo
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmidt
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Nadine
authors.initials: N
authors.lastname: Mrad
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Chu Kong
authors.initials: CK
authors.lastname: Liew
authors.affiliation: Department of Pharmacology, School of Medical Sciences, University of New South Wales, Kensington, New South Wales 2033, Australia.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Jones
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Graham
authors.affiliation: Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales 2010, Australia. St Vincent's Clinical School, University of New South Wales, Darlinghurst, New South Wales 2010, Australia. n.smith@victorchang.edu.au.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Smith
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008297:Male; D045726:Metalloproteases / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: C111572:GPR37L1 protein, human; D050505:Mutant Proteins; D043562:Receptors, G-Protein-Coupled; D045726:Metalloproteases; D051722:ADAM Proteins; D019205:GTP-Binding Protein alpha Subunits, Gs