Tetraspanin‐7 regulation of L‐type voltage‐dependent calcium channels controls pancreatic β‐cell insulin secretion
Key points Tetraspanin (TSPAN) proteins regulate many biological processes, including intracellular calcium (Ca2+) handling. TSPAN‐7 is enriched in pancreatic islet cells; however, the function of islet TSPAN‐7 has not been identified. Here, we characterize how β‐cell TSPAN‐7 regulates Ca2+ handling and hormone secretion. We find that TSPAN‐7 reduces β‐cell glucose‐stimulated Ca2+ entry, slows Ca2+ oscillation frequency and decreases glucose‐stimulated insulin secretion. TSPAN‐7 controls β‐cell function through a direct interaction with L‐type voltage‐dependent Ca2+ channels (Ca V1.2 and Ca V1.3), which reduces channel Ca2+ conductance. TSPAN‐7 slows activation of Ca V1.2 and accelerates recovery from voltage‐dependent inactivation; TSPAN‐7 also slows Ca V1.3 inactivation kinetics. These findings strongly implicate TSPAN‐7 as a key regulator in determining the set‐point of glucose‐stimulated Ca2+ influx and insulin secretion. Abstract 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 V1.2 and Ca V1.3 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 V1.2 and Ca V1.3 from primary human β‐cells and from a heterologous expression system. Finally, TSPAN‐7 KD in human β‐cells increased basal (5.6 m M glucose) and stimulated (45 m M KCl + 14 m M 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..
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:598 |
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| Enthalten in: |
The Journal of Physiology - 598(2020), 21, Seite 4887-4905 |
| Beteiligte Personen: |
Dickerson, Matthew T. [VerfasserIn] |
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| BKL: |
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| Anmerkungen: |
Journal compilation © 2020 The Physiological Society |
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| Umfang: |
19 |
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| doi: |
10.1113/JP279941 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Dickerson, Matthew T. |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Tetraspanin‐7 regulation of L‐type voltage‐dependent calcium channels controls pancreatic β‐cell insulin secretion |
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| 520 | |a Key points Tetraspanin (TSPAN) proteins regulate many biological processes, including intracellular calcium (Ca2+) handling. TSPAN‐7 is enriched in pancreatic islet cells; however, the function of islet TSPAN‐7 has not been identified. Here, we characterize how β‐cell TSPAN‐7 regulates Ca2+ handling and hormone secretion. We find that TSPAN‐7 reduces β‐cell glucose‐stimulated Ca2+ entry, slows Ca2+ oscillation frequency and decreases glucose‐stimulated insulin secretion. TSPAN‐7 controls β‐cell function through a direct interaction with L‐type voltage‐dependent Ca2+ channels (Ca V1.2 and Ca V1.3), which reduces channel Ca2+ conductance. TSPAN‐7 slows activation of Ca V1.2 and accelerates recovery from voltage‐dependent inactivation; TSPAN‐7 also slows Ca V1.3 inactivation kinetics. These findings strongly implicate TSPAN‐7 as a key regulator in determining the set‐point of glucose‐stimulated Ca2+ influx and insulin secretion. Abstract 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 V1.2 and Ca V1.3 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 V1.2 and Ca V1.3 from primary human β‐cells and from a heterologous expression system. Finally, TSPAN‐7 KD in human β‐cells increased basal (5.6 m M glucose) and stimulated (45 m M KCl + 14 m M 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. | ||
| 700 | 1 | |a Dadi, Prasanna K. |4 aut | |
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| 700 | 1 | |a Zaborska, Karolina E. |4 aut | |
| 700 | 1 | |a Schaub, Charles M. |4 aut | |
| 700 | 1 | |a Jacobson, David A. |4 aut | |
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