Adhesion G Protein-Coupled Receptors as Drug Targets for Neurological Diseases

Christopher J Folts; Stefanie Giera; Tao Li; Xianhua Piao

doi:10.1016/j.tips.2019.02.003

Adhesion G Protein-Coupled Receptors as Drug Targets for Neurological Diseases

Trends Pharmacol Sci. 2019 Apr;40(4):278-293. doi: 10.1016/j.tips.2019.02.003. Epub 2019 Mar 11.

Authors

Christopher J Folts¹, Stefanie Giera², Tao Li³, Xianhua Piao⁴

Affiliations

¹ Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Current address: Vertex Pharmaceuticals, 50 Northern Avenue, Boston, MA 02210, USA.
² Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Current address: Sanofi S.A., 49 New York Avenue, Framingham, MA 01701, USA.
³ Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; Newborn Brain Research Institute, University of California at San Francisco, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: xianhua.piao@ucsf.edu.

Abstract

The family of adhesion G protein-coupled receptors (aGPCRs) consists of 33 members in humans. Although the majority are orphan receptors with unknown functions, many reports have demonstrated critical functions for some members of this family in organogenesis, neurodevelopment, myelination, angiogenesis, and cancer progression. Importantly, mutations in several aGPCRs have been linked to human diseases. The crystal structure of a shared protein domain, the GPCR Autoproteolysis INducing (GAIN) domain, has enabled the discovery of a common signaling mechanism - a tethered agonist - for this class of receptors. A series of recent reports has shed new light on their biological functions and disease relevance. This review focuses on these recent advances in our understanding of aGPCR biology in the nervous system and the untapped potential of aGPCRs as novel therapeutic targets for neurological disease.

Keywords: GAIN domain; GPCR Autoproteolysis INducing domain; adhesion G protein-coupled receptors; neurodevelopment; neurological disease.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Drug Development / methods
Humans
Molecular Targeted Therapy*
Mutation
Nervous System Diseases / drug therapy*
Nervous System Diseases / genetics
Nervous System Diseases / physiopathology
Receptors, G-Protein-Coupled / drug effects
Receptors, G-Protein-Coupled / genetics
Receptors, G-Protein-Coupled / metabolism*
Signal Transduction

Substances

Receptors, G-Protein-Coupled

Abstract

Publication types

MeSH terms

Substances

Grants and funding