Tsang Choi Har, De Rosa Alexander, Kozielewicz Paweł
Molecular Pharmacology of GPCRs, Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden.
Molecular Pharmacology of GPCRs, Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden; School of Engineering Sciences (SCI), KTH Royal Institute of Technology, Stockholm, Sweden.
Mol Pharmacol. 2025 Apr;107(4):100026. doi: 10.1016/j.molpha.2025.100026. Epub 2025 Mar 4.
Severe obesity is a complex chronic metabolic condition with a body mass index over 40 and can be caused, for example, by dysregulated G protein-coupled receptors (GPCRs) signaling. The orphan GPCR GPR61 had been linked to the regulation of metabolism and, here, we identify 34 mutations in the GPR61 gene which are present with much higher frequency in severe obesity samples from the UK10K obesity screen compared to the normal population. Furthermore, the cumulative sum of GPR61 mutations was found to be higher compared to the highly mutated and well-established target, melanocortin 4 receptor. Some GPR61 mutations presented an impact on ligand-independent GPR61-induced cAMP production. Specifically, R236C compromised G protein activation and altered the pattern of cellular expression. Our data warrant further studies to assess the role of this orphan GPCR in metabolism in greater detail. SIGNIFICANCE STATEMENT: This study identified missense mutations, including previously unknown variants, of the GPR61 gene in severely obese patients. This occurrence was higher than for the well-established obesity target melanocortin 4 receptor. In the in vitro assays, 3 mutations of GPR61, in particular R236C, were loss of function because they reduced the constitutive activity of the receptor. The data support the notion that GPR61 can act as a promising target in obesity and its functions should be explored in future studies.
重度肥胖是一种复杂的慢性代谢疾病，体重指数超过40，例如可能由G蛋白偶联受体（GPCR）信号失调引起。孤儿GPCR GPR61与代谢调节有关，在此我们鉴定出GPR61基因中的34个突变，这些突变在英国10K肥胖筛查的重度肥胖样本中的出现频率远高于正常人群。此外，与高度突变且已明确的靶点黑皮质素4受体相比，发现GPR61突变的累积总和更高。一些GPR61突变对非配体依赖性GPR61诱导的cAMP产生有影响。具体而言，R236C损害了G蛋白激活并改变了细胞表达模式。我们的数据需要进一步研究，以更详细地评估这种孤儿GPCR在代谢中的作用。意义声明：本研究在重度肥胖患者中鉴定出GPR61基因的错义突变，包括先前未知的变体。这种情况比已明确的肥胖靶点黑皮质素4受体更高。在体外试验中，GPR61的3个突变，特别是R236C，功能丧失，因为它们降低了受体的组成性活性。这些数据支持GPR61可以作为肥胖症中有前景的靶点这一观点，其功能应在未来研究中进行探索。
