Dehkhoda Farhad, Ringuet Mitchell T, Whitfield Emily A, Mutunduwe Keith, Whelan Fiona, Nowell Cameron J, Misganaw Desye, Xu Zheng, Piper Noah B C, Clark Richard J, Hossain Mohammed Akhter, Fothergill Linda J, McDougall Stuart J, Furness John B, Furness Sebastian G B
School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia.
Department of Anatomy & Physiology, University of Melbourne, Melbourne, VIC, Australia.
Mol Cell. 2025 Jun 5;85(11):2246-2260.e10. doi: 10.1016/j.molcel.2025.05.005. Epub 2025 May 28.
Changes in cellular output from one G protein-coupled receptor in another's presence have been attributed to dimerization and/or signal crosstalk. However, data distinguishing models are often lacking, and, in many cases, the molecular basis remains controversial. One such interaction is the reversal, inhibition to excitation, at the dopamine D2 receptor in the ghrelin receptor's presence in the spinal defecation center. This reversal is required for the physiological control of defecation, where dopamine is the relevant neurotransmitter. Using native neurons from mice and recombinant cells, we show that this reversal of dopamine D2 activity occurs downstream of calcium mobilization through a dominant signaling switch. Our results show that this reversal is a consequence of the ghrelin receptor's constitutive activity, where neither its agonism nor dimerization with the D2 receptor is required, in the systems tested. Dependence on constitutive activity may account for conservation of central-nervous-system ghrelin receptor in the absence of endogenous agonist.
在另一种G蛋白偶联受体存在的情况下，一种G蛋白偶联受体的细胞输出变化被归因于二聚化和/或信号串扰。然而，区分模型的数据往往缺乏，而且在许多情况下，分子基础仍存在争议。一种这样的相互作用是在脊髓排便中枢中，胃饥饿素受体存在时多巴胺D2受体的作用逆转，即从抑制转变为兴奋。这种逆转对于排便的生理控制是必需的，其中多巴胺是相关的神经递质。利用来自小鼠的原代神经元和重组细胞，我们表明多巴胺D2活性的这种逆转发生在钙动员的下游，通过一个显性信号开关实现。我们的结果表明，这种逆转是胃饥饿素受体组成性活性的结果，在所测试的系统中，既不需要其激动作用，也不需要与D2受体二聚化。对组成性活性的依赖可能解释了在没有内源性激动剂的情况下中枢神经系统胃饥饿素受体的保守性。
