GPCRs regulating catecholaminergic cell survival and function : focus on GPR37

Abstract: Dysfunction and dysregulation of catecholaminergic signaling are major causes of many neurological and psychiatric disorders, including Parkinson’s disease (PD), schizophrenia, ADHD and drug addiction. Currently an incomplete understanding of the mechanisms regulating the function and survival of catecholaminergic neurons hinders the development of effective treatments. Catecholaminergic signal transmission is entirely mediated by G protein-coupled receptors (GPCRs), and many other GPCRs are involved in the regulation of catecholaminergic function. GPCRs have an outstanding potential as drug targets, and the work behind this thesis was therefore focused on improving the understanding of how two GPCRs, GPR37 and TAAR1, regulate the survival and function of catecholaminergic cells. Our main findings relate to the effects of GPR37 on catecholaminergic cell survival with potential implications for the progression of PD. Death of dopaminergic neurons in the substantia nigra causes many symptoms in PD. GPR37 accumulates in the substantia nigra of PD patients, and is implicated in the pathogenesis due to its high propensity to misfold, aggregate and thereby cause cell death. In contrast to the neurotoxic GPR37 aggregates, we found that GPR37 in the plasma membrane improves cellular resistance to PD-inducing toxins. Shortly after this discovery, the neurotrophic and neuroprotective protein prosaposin (PSAP) and its synthetic peptide derivatives, prosaptides, were identified as agonists at GPR37. We could confirm binding of prosaptide to GPR37 in live N2a cells, but not interactions of GPR37 with another proposed peptide ligand, head activator. We further found that N2a cells secrete PSAP, and that GPR37 at least in part mediates the neurotrophic effects of PSAP in N2a cells. Moreover, extracellular PSAP promotes membrane association of GPR37 and partitioning of GPR37 into GM1 ganglioside-enriched lipid rafts where it forms complexes with GM1. Lipid rafts are crucial for the neurotrophic properties of PSAP and prosaptides, and GM1 treatment ameliorates the progression of PD. The PSAP-induced partitioning of GPR37 into lipid rafts and the observed interactions of GPR37 with both prosaptide and GM1 thus suggest that lipid rafts provide a scaffold through which PSAP, GPR37 and GM1 may interact to improve neuronal viability. Collectively, the results on GPR37 indicate that promotion of GPR37 density in the plasma membrane versus the cytoplasm, rather than an overall reduction of GPR37 levels, could delay progressive death of dopaminergic neurons. They further identify a pathway involving PSAP and GM1 that could be targeted to modulate sorting of GPR37 between the plasma membrane and the cytoplasm, and to improve neuroprotective effects of GPR37. Future studies now need to address the mechanistic details of this pathway and its relevance to dopaminergic neuronal survival in the brain. TAAR1 modulates dopaminergic signaling via various pathways and has been implicated in neuropsychiatric disorders such as schizophrenia, bipolar disorder and ADHD as well as in psychostimulant addiction. The receptor binds amphetamines, including MDMA, with high affinity. Here we found that genetic deletion of TAAR1 in mice enhanced effects of MDMA on dopamine release and production as well as on thermoregulation and motor behavior. Overall, MDMA appeared to autoinhibit its own actions via TAAR1, and potentiation of TAAR1 signaling may thus be beneficial in the treatment of psychostimulant addiction. Both GPR37 and TAAR1 are interesting receptors not only due to their relevance to disease but also due to their unconventional trafficking and signaling properties. This thesis thus provides novel information on GPCR functioning with potential implications for the development of novel treatments in PD and drug addiction.