Abstract
Orphan G protein-coupled receptors (GPCRs) represent a largely untapped resource for the treatment of a variety of diseases, despite sophisticated advances in drug discovery. Two promising orphan GPCRs are the endothelin B receptor-like proteins, GPR37 [ET(B)R-LP, Pael-R] and GPR37L1 [ET(B)R-LP-2]. Originally identified through searches for homologs of endothelin and bombesin receptors, neither GPR37 nor GPR37L1 were found to bind endothelins or related peptides. Instead, GPR37 was proposed to be activated by head activator (HA) and both GPR37 and GPR37L1 have been linked to the neuropeptides prosaposin and prosaptide, although these pairings are yet to be universally acknowledged. Both orphan GPCRs are widely expressed in the brain, where GPR37 has received the most attention for its link to Parkinson’s disease and parkinsonism, while GPR37L1 deletion leads to precocious cerebellar development and hypertension. In this review, the existing pharmacology and physiology of GPR37 and GPR37L1 is discussed and the potential therapeutic benefits of targeting these receptors are explored.
Highlights
G protein-coupled receptors (GPCRs) are a family of seven transmembrane (TM)-spanning proteins that transmit responses from the extracellular milieu by binding to a variety of different ligands, including neurotransmitters, lipids, peptides, protons, odorants, and light
Further links between GPR37 and contactin-associated proteinlike 2 (CASPR2), which has itself been linked to autism spectrum disorder (ASD) (Bakkaloglu et al, 2008), were not examined and further study is clearly required to understand whether GPR37 mutations contribute to the complex phenotype of ASD
Western blots of various components of the sonic hedgehog (Shh) pathway revealed altered expression in GPR37L1 KOs during P5, P10 and P15, key stages of cerebellar development, while GPR37L1 was found to interact with the Shh receptor, patched-1, by co-immunoprecipitation from wild type tissue (Marazziti et al, 2013). Not surprisingly, such marked changes in cerebellar development translated into phenotypic differences in behavioral tests—GPR37L1 KO mice had enhanced motor skills when assessed for rotarod, negative geotaxis, climbing reflex and wire hanging performance (Marazziti et al, 2013)
Summary
G protein-coupled receptors (GPCRs) are a family of seven transmembrane (TM)-spanning proteins that transmit responses from the extracellular milieu by binding to a variety of different ligands, including neurotransmitters, lipids, peptides, protons, odorants, and light. They are considered to be ideal drug targets because of their propensity to bind and respond to agonists, antagonists and allosteric modulators, facilitating a plethora of functional outcomes. The discovery, description and possible therapeutic application of two endothelin B receptor-like peptide family GPCRs, GPR37 and GPR37L1, will be described
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