Abstract

Somatostatin receptor subtype 5 (SSTR5), a G protein-coupled receptor (GPCR) highly expressed in the pituitary gland, plays a pivotal role in regulating adrenocorticotropic hormone (ACTH) secretion. While SSTR5 homodimerization has been observed in heterologous expression systems, its in situ existence, structural dynamics, and functional relevance in clinical pathology remain elusive. In this study, we provide the first evidence of endogenous SSTR5 homodimers in human corticotroph adenomas. Further analysis reveals that SSTR5 dimerization is mediated by multiple transmembrane (TM) interfaces and, uniquely among GPCRs, lacks ligand-induced conformational rearrangement. Functionally, we demonstrate that a stabilized dimeric conformation induces signaling bias by impairing both constitutive Gi protein activation and agonist-induced beta-arrestin2 recruitment. In cellular models of corticotroph adenomas, SSTR5 dimerization significantly attenuates the receptor's capacity to suppress hormone secretion and diminishes responsiveness to the clinical agonist pasireotide. Furthermore, we identified a natural genetic variant (V270I) that modulates dimerization efficiency, potentially serving as a biomarker for therapeutic sensitivity. Collectively, these findings establish SSTR5 homodimerization as a critical determinant of receptor signaling and a key modulator of pharmacological efficacy in the treatment of corticotroph adenomas. Graphical The graphical abstract illustrates SSTR5 homodimerization via transmembrane helices TM1,3,4,5,6,7 at the dimer interface. Compared with the monomer, the dimer exhibits reduced constitutive activation, comparable G protein activation upon agonist stimulation, but impaired β-arrestin recruitment. In ACTH-secreting pituitary adenomas, SSTR5 dimerization elevates basal ACTH levels while preserving responsiveness to agonist-based pharmacotherapy.