GPR37 is an orphan G-protein coupled receptor highly expressed in the mammalian central nervous system that has been shown to be a substrate of parkin (parkin associated endothelin-like receptor; PAEL-R). An insoluble form of the GPR37/PAEL-R was found accumulated in brain samples of Parkinson's disease patients and GPR37/PAEL-R overexpression in cell cultures, in the absence of parkin, can lead to unfolded protein-induced cell death. To investigate the receptor's function, we generated homozygous Gpr37 null mice. Gpr37-/- mice are viable, with normal brain development and no gross morpho-anatomical abnormalities. They exhibit a reduction in the striatal dopamine content, an increased sensitivity to amphetamine treatment and resistance to nigro-striatal dopaminergic cell degeneration induced by MPTP treatment. The null mutant mice also show specific locomotor, motor coordination and sensorimotor deficits in behavior paradigms that are sensitive to dysfunction of the substantia nigra (SN) -striatum dopaminergic signalling, such as the open field, rotarod and acoustic startle response tests. We suggest that GPR37/PAEL-R is involved in the network of components that regulate the functionality of the nigro-striatal dopaminergic pathway. Biochemical and behavioural analyses are now being assessed to study functional alterations of striatal dopamine receptors, as well as dopamine transporter and vesicular monoamine transporter in Gpr37-/- mice. Parallel behavioral analyses focus on studying null mutant mice responses to specific dopamine receptors antagonists (haloperidol and SCH23390) by the catalepsy bar test. The behavioral and neurochemical analysis of Gpr37-/- mice will clarify the role of GPR37 in the regulation of dopaminergic systems and its involvement in the molecular mechanisms underlying the pathophysiology of Parkinson's disease. Supported by MIUR-CNR, MIUR FIRB and EUMORPHIA and MUGEN European Networks of Excellence.
GPR37/PAEL-R interacts with the dopamine transporter and alters dopaminergic signalling in the nigro-striatal pathway
Golini E;Mandillo S;Marazziti D;Di Pietro C;Matteoni R;
2006
Abstract
GPR37 is an orphan G-protein coupled receptor highly expressed in the mammalian central nervous system that has been shown to be a substrate of parkin (parkin associated endothelin-like receptor; PAEL-R). An insoluble form of the GPR37/PAEL-R was found accumulated in brain samples of Parkinson's disease patients and GPR37/PAEL-R overexpression in cell cultures, in the absence of parkin, can lead to unfolded protein-induced cell death. To investigate the receptor's function, we generated homozygous Gpr37 null mice. Gpr37-/- mice are viable, with normal brain development and no gross morpho-anatomical abnormalities. They exhibit a reduction in the striatal dopamine content, an increased sensitivity to amphetamine treatment and resistance to nigro-striatal dopaminergic cell degeneration induced by MPTP treatment. The null mutant mice also show specific locomotor, motor coordination and sensorimotor deficits in behavior paradigms that are sensitive to dysfunction of the substantia nigra (SN) -striatum dopaminergic signalling, such as the open field, rotarod and acoustic startle response tests. We suggest that GPR37/PAEL-R is involved in the network of components that regulate the functionality of the nigro-striatal dopaminergic pathway. Biochemical and behavioural analyses are now being assessed to study functional alterations of striatal dopamine receptors, as well as dopamine transporter and vesicular monoamine transporter in Gpr37-/- mice. Parallel behavioral analyses focus on studying null mutant mice responses to specific dopamine receptors antagonists (haloperidol and SCH23390) by the catalepsy bar test. The behavioral and neurochemical analysis of Gpr37-/- mice will clarify the role of GPR37 in the regulation of dopaminergic systems and its involvement in the molecular mechanisms underlying the pathophysiology of Parkinson's disease. Supported by MIUR-CNR, MIUR FIRB and EUMORPHIA and MUGEN European Networks of Excellence.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
