Institute of Metabolism and Systems Research and Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK.
Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham, UK.
J Endocrinol. 2021 Nov 24;252(1):R23-R39. doi: 10.1530/JOE-21-0206.
Ghrelin is a peptide hormone secreted primarily by the stomach that acts upon the growth hormone secretagogue receptor (GHSR1), a G protein-coupled receptor whose functions include growth hormone secretion, appetite regulation, energy expenditure, regulation of adiposity, and insulin release. Following the discovery that GHSR1a stimulates food intake, receptor antagonists were developed as potential therapies to regulate appetite. However, despite reductions in signalling, the desired effects on appetite were absent. Studies in the past 15 years have demonstrated GHSR1a can interact with other transmembrane proteins, either by direct binding (i.e. heteromerisation) or via signalling cross-talk. These interactions have various effects on GHSR1a signalling including preferential coupling to one pathway (i.e. biased signalling), coupling to a unique G protein (G protein switching), suppression of GHSR1a signalling, and enhancement of signalling by both receptors. While many of these interactions have been shown in cells overexpressing the proteins of interest and remain to be verified in tissues, substantial evidence exists showing that GHSR1a and the dopamine receptor D1 (DRD1) form heteromers, which promote synaptic plasticity and formation of hippocampal memory. Additionally, a reduction in GHSR1a-DRD1 complexes in favour of establishment of GHSR1a-Aβ complexes correlates with Alzheimer's disease, indicating that GHSR1a heteromers may have pathological functions. Herein, we summarise the evidence published to date describing interactions between GHSR1a and transmembrane proteins, discuss the experimental strengths and limitations of these studies, describe the physiological evidence for each interaction, and address their potential as novel drug targets for appetite regulation, Alzheimer's disease, insulin secretion, and inflammation.
胃泌素是一种主要由胃分泌的肽类激素，作用于生长激素促分泌素受体（GHSR1），GHSR1 是一种 G 蛋白偶联受体，其功能包括生长激素分泌、食欲调节、能量消耗、脂肪量调节和胰岛素释放。在发现 GHSR1a 刺激摄食后，开发了受体拮抗剂作为调节食欲的潜在治疗方法。然而，尽管信号减少，对食欲的期望效果却没有出现。过去 15 年的研究表明，GHSR1a 可以与其他跨膜蛋白相互作用，通过直接结合（即异源二聚化）或通过信号转导交叉对话。这些相互作用对 GHSR1a 信号具有各种影响，包括优先与一种途径偶联（即偏向性信号转导）、与独特的 G 蛋白偶联（G 蛋白转换）、抑制 GHSR1a 信号转导以及两种受体的信号转导增强。虽然许多这些相互作用已经在过表达感兴趣的蛋白质的细胞中显示，并且仍有待在组织中验证，但大量证据表明 GHSR1a 和多巴胺受体 D1（DRD1）形成异源二聚体，促进突触可塑性和海马记忆的形成。此外，GHSR1a-DRD1 复合物的减少有利于 GHSR1a-Aβ 复合物的建立与阿尔茨海默病相关，表明 GHSR1a 异源二聚体可能具有病理功能。在此，我们总结了迄今为止发表的描述 GHSR1a 与跨膜蛋白相互作用的证据，讨论了这些研究的实验优势和局限性，描述了每种相互作用的生理证据，并探讨了它们作为调节食欲、阿尔茨海默病、胰岛素分泌和炎症的新型药物靶点的潜力。
