Syndecans modulate ghrelin receptor signaling

Ghrelin is a gut hormone that enhances food intake and growth hormone secretion through its G-protein coupled receptor, the growth hormone secretagogue receptor (GHSR). Recently, we have shown that ghrelin interacts with syndecans (SDCs), a family of membrane proteins known to modulate hypothalamic appetite signaling. Here, we investigated whether SDCs impact ghrelin signaling at GHSR by assessing ghrelin-induced intracellular Ca²⁺ mobilization (iCa²⁺) and inositol phosphate 1 (IP1) production in HEK293 cells. Compared with controls, the overexpression of SDCs dose-dependently increased the maximum iCa²⁺ response two-to four-fold, without affecting EC₅₀. The IP1 response was similarly amplified by SDCs, but it also indicated that they reduce constitutive (ghrelin-independent) activity of GHSR. These enhanced responses occurred despite a SDC dose-dependent reduction in plasma membrane GHSR levels. Although ghrelin-stimulated Gα_q activation was unaltered by SDC1 expression, it failed to restore iCa²⁺ responsiveness in GNAQ/11 knockout cells, indicating dependence on Gα_q/11, not another Gα subunit. This suggests that SDCs modulate either signaling downstream of Gα_q/11 or quenching of b-arrestin2 recruitment to GHSR. Indeed, expression of SDCs at levels that only modestly suppress cell surface receptor reduced ghrelin-induced b-arrestin2 recruitment by ∼80%. SDC co-expression also delayed the peak b-arrestin2 response. However, peak b-arrestin2 recruitment follows the peak iCa²⁺ response, making it unclear whether reduced b-arrestin2 recruitment potentiated Ca²⁺ signaling. Altogether, SDCs enhanced iCa²⁺/IP1 and reduced b-arrestin2 recruitment by GHSR in response to ghrelin, likely by modulating signaling downstream of Gα_q. This could be a novel mechanism through which SDCs affect metabolism and obesity.