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N-Type Ca²⁺-Channels in Murine Pancreatic β-Cells Are Inhibited by an Exclusive Coupling with Somatostatin Receptor Subtype 1

School of Biomedical Sciences, Queens Medical Centre, Nottingham NG7 2UH, United Kingdom

Address all correspondence and requests for reprints to: Dr. P. A. Smith, School of Biomedical Sciences, Queens Medical Centre, Nottingham NG7 2UH, United Kingdom. E-mail: paul.a.smith{at}nottingham.ac.uk.

Somatostatin (SRIF) is a well-established inhibitor of insulin secretion, an effect in part mediated by a direct inhibition of voltage-operated Ca²⁺-channels. However, the identity of the somatostatin receptor subtypes (SSTRs) and voltage-operated Ca²⁺-channels involved in this process are unknown. Whole-cell perforated patch-clamp methods were applied to the murine pancreatic β-cell line, MIN6, to explore the molecular pharmacology of this problem. SRIF-14 inhibited voltage-gated Ca²⁺ currents (ICa²⁺) by 19 ± 3% (n=24) with a pEC₅₀ = 9.05 (95% confidence limits 9–9.1). This action was mimicked solely by 100 nM CH-275, a selective agonist at the somatostatin type 1 receptor (SSTR1), but not by 100 nM BIM-23027, L-362855, or NNC-269100; agonists selective for the other four SSTRs known to exist in MIN6. The inhibition of ICa²⁺ produced by SRIF and CH-275 was insensitive to pertussis toxin but was reversed by a prepulse to +100 mV. The inhibition of ICa²⁺ by SRIF-14 was unaffected by 20 µM nifedipine, an inhibitor of L-type Ca²⁺ channels. Application of the specific N-type Ca²⁺ channel (Ca_v2.2) inhibitor -conotoxin GV1A at 100 nM mimicked, and as a consequence abolished, the inhibitory effect of SRIF-14 on ICa²⁺. SRIF selectively inhibits N-type Ca²⁺-channels in murine pancreatic β-cells via exclusive coupling with SSTR1. These findings help explain how SSTR1 activation can inhibit insulin secretion in pancreatic β-cells and suggest a possible new therapeutic lead for treatment of hyperinsulinemia.