TALK-1 reduces delta-cell endoplasmic reticulum and cytoplasmic calcium levels limiting somatostatin secretion

OBJECTIVE: Single-cell RNA sequencing studies have revealed that the type-2 diabetes associated two-pore domain K(+) (K2P) channel TALK-1 is abundantly expressed in somatostatin-secreting δ-cells. However, a physiological role for TALK-1 in δ-cells remains unknown. We previously determined that in β-cells, K(+) flux through endoplasmic reticulum (ER)-localized TALK-1 channels enhances ER Ca(2+) leak, modulating Ca(2+) handling and insulin secretion. As glucose amplification of islet somatostatin release relies on Ca(2+)-induced Ca(2+) release (CICR) from the δ-cell ER, we investigated whether TALK-1 modulates δ-cell Ca(2+) handling and somatostatin secretion. METHODS: To define the functions of islet δ-cell TALK-1 channels, we generated control and TALK-1 channel-deficient (TALK-1 KO) mice expressing fluorescent reporters specifically in δ- and α-cells to facilitate cell type identification. Using immunofluorescence, patch clamp electrophysiology, Ca(2+) imaging, and hormone secretion assays, we assessed how TALK-1 channel activity impacts δ- and α-cell function. RESULTS: TALK-1 channels are expressed in both mouse and human δ-cells, where they modulate glucose-stimulated changes in cytosolic Ca(2+) and somatostatin secretion. Measurement of cytosolic Ca(2+) levels in response to membrane potential depolarization revealed enhanced CICR in TALK-1 KO δ-cells that could be abolished by depleting ER Ca(2+) with sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA) inhibitors. Consistent with elevated somatostatin inhibitory tone, we observed significantly reduced glucagon secretion and α-cell Ca(2+) oscillations in TALK-1 KO islets, and found that blockade of α-cell somatostatin signaling with a somatostatin receptor 2 (SSTR2) antagonist restored glucagon secretion in TALK-1 KO islets. CONCLUSIONS: These data indicate that TALK-1 reduces δ-cell cytosolic Ca(2+) elevations and somatostatin release by limiting δ-cell CICR, modulating the intraislet paracrine signaling mechanisms that control glucagon secretion.