A structural overview of G-protein-coupled receptors in neurological disorders

Neuropsychiatry and neurodegenerative disorders (NPDs and NDDs) are often associated with various physiological factors. It is increasingly apparent that signal transducers like G-protein-coupled receptors (GPCRs) are critical in disease progression and constitute an important class of drug targets. Several members of class A, class B, and class C GPCR families, along with their cognate binding partners, are involved in neurotransmission and neuromodulation. The vast information about the different molecular states of these GPCRs with their signaling complexes unravels the understanding of residual specificity in these protein-protein interactions and the dynamicity of transmembrane helices. The atypical mode of interaction of GPCRs with binding partners provides valuable insights for GPCR-conformation-based drug designing. In this review, we highlight the structural features of the serotonin, dopamine, and corticotropin receptors, namely 5-HTR_1A, 5-HTR_1B, 5-HTR_2A, 5-HTR_2B, 5-HTR_2C, 5-HTR₄, 5-HTR₆, 5-HTR₇, D_1-5R, and CRF_1-2R when forming transient complexes with G-proteins and arrestins. The distinct structural characteristics of these receptors explain the underlying molecular mechanism for signaling specificity and related physiological processes. This review also summarizes the importance of these structural insights in developing newer and effective pharmacologically biased drugs that can mediate specific signaling pathways to GPCRs.