Glucose-stimulated insulin secretion (GSIS) is regulated by calcium (Ca²⁺ ) entry into pancreatic β-cells through voltage-dependent Ca²⁺ (Ca_V ) channels. Tetraspanin (TSPAN) transmembrane proteins control Ca²⁺ handling, and thus they may also modulate GSIS. TSPAN-7 is the most abundant islet TSPAN and immunostaining of mouse and human pancreatic slices shows that TSPAN-7 is highly expressed in β- and α-cells; however, the function of islet TSPAN-7 has not been determined. Here, we show that TSPAN-7 knockdown (KD) increases glucose-stimulated Ca²⁺ influx into mouse and human β-cells. Additionally, mouse β-cell Ca²⁺ oscillation frequency was accelerated by TSPAN-7 KD. Because TSPAN-7 KD also enhanced Ca²⁺ entry when membrane potential was clamped with depolarization, the effect of TSPAN-7 on Ca_V channel activity was examined. TSPAN-7 KD enhanced L-type Ca_V currents in mouse and human β-cells. Conversely, heterologous expression of TSPAN-7 with Ca_V 1.2 and Ca_V 1.3 L-type Ca_V channels decreased Ca_V currents and reduced Ca²⁺ influx through both channels. This was presumably the result of a direct interaction of TSPAN-7 and L-type Ca_V channels because TSPAN-7 coimmunoprecipitated with both Ca_V 1.2 and Ca_V 1.3 from primary human β-cells and from a heterologous expression system. Finally, TSPAN-7 KD in human β-cells increased basal (5.6 mM glucose) and stimulated (45 mM KCl + 14 mM glucose) insulin secretion. These findings strongly suggest that TSPAN-7 modulation of β-cell L-type Ca_V channels is a key determinant of β-cell glucose-stimulated Ca²⁺ entry and thus the set-point of GSIS.

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