| First Author | Vierra NC | Year | 2018 |
| Journal | Mol Metab | Volume | 9 |
| Pages | 84-97 | PubMed ID | 29402588 |
| Mgi Jnum | J:306486 | Mgi Id | MGI:6709569 |
| Doi | 10.1016/j.molmet.2018.01.016 | Citation | Vierra NC, et al. (2018) TALK-1 reduces delta-cell endoplasmic reticulum and cytoplasmic calcium levels limiting somatostatin secretion. Mol Metab 9:84-97 |
| abstractText | 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 delta-cells. However, a physiological role for TALK-1 in delta-cells remains unknown. We previously determined that in beta-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 delta-cell ER, we investigated whether TALK-1 modulates delta-cell Ca(2+) handling and somatostatin secretion. METHODS: To define the functions of islet delta-cell TALK-1 channels, we generated control and TALK-1 channel-deficient (TALK-1 KO) mice expressing fluorescent reporters specifically in delta- and alpha-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 delta- and alpha-cell function. RESULTS: TALK-1 channels are expressed in both mouse and human delta-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 delta-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 alpha-cell Ca(2+) oscillations in TALK-1 KO islets, and found that blockade of alpha-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 delta-cell cytosolic Ca(2+) elevations and somatostatin release by limiting delta-cell CICR, modulating the intraislet paracrine signaling mechanisms that control glucagon secretion. |
