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GPRC6A is acknowledged as a major regulator of energy metabolism and male fertility through the action of undercarboxylated osteocalcin (ucOCN), representing a possible therapeutic target. We recently showed that the sex hormone-binding globulin (SHBG) binds to GPRC6A through the likely involvement of the 141–161 domain. To confirm this model, here we investigated the possible binding and agonist activity of SHBG(141–161) domain-peptide (SHBG 141–161 ) on GPRC6A. The binding of SHBG 141–161  to GPRC6A and downstream dissociation from G αi (GDP) protein was computationally modelled. SHBG 141–161  was obtained by solid-phase synthesis, characterized by circular dichroism (CD) and the receptor binding was assessed by displacement of ucOCN on HEK-293 cells transfected with  GPRC6A  gene. Agonist activity of SHBG 141–161  was assessed on Leydig MA-10 and Langerhans β-TC6 cell lines through the GPRC6A-mediated release of testosterone (T) and insulin. SHBG 141–161  was predicted to bind to GPRC6A and to reduce the affinity for G αi (GDP) at computational level. Conformational properties and binding to GPRC6A of the synthetic SHBG 141–161  were confirmed by CD and displacement experiments. SHBG 141–161  stimulated cell secretion of T and insulin, with dose dependency from 10 −13  to 10 −11 M for T release (respectively P = 0,041 10 −13 M; P = 0,032 10 −12 M; P = 0,008 10 −11 M  vs  basal) and for 10 −12  to 10 −10 M for insulin (respectively P = 0,041 10 −12 M; P = 0,007 10 −11 M; P = 0,047 10 −10 M; P = 0,045  vs  basal). Blockade with anti GPRC6A IgG abolished the response to SHBG 141-161 , suggesting agonist specificity. SHBG 141–161  showed stimulating activity on GPRC6A, representing a template peptide with possible therapeutic use for metabolic and endocrine disorders.

SHBG141–161 Domain-Peptide Stimulates GPRC6A-Mediated Response in Leydig and β-Langerhans cell lines