A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young

Abstract

Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic disorders of impaired pancreatic β-cell function. One of the mechanisms results from β-cell K ATP channel dysfunction (e.g., KCNJ11 (MODY13) or ABCC8 (MODY12) mutations); however, no other β-cell channelopathies have been identified in MODY. We identified a previously unreported non-synonymous coding variant in KCNK16 (NM_001135105: c.341T>C, p.Leu114Pro) segregating with MODY. KCNK16 is the most abundant and -cell-restricted K + channel transcript and encodes the two-pore-domain K + channel TALK-1. Wholecell K + currents demonstrated a large gain-of-function with TALK-1 Leu114Pro vs. WT, due to greater single channel activity. Glucose-stimulated membrane potential depolarization and Ca 2+ influx was inhibited in mouse islets expressing TALK-1 Leu114Pro (area under the Ca 2+ curve [AUC] at 20mM glucose: Leu114Pro 60.1 vs. WT 89.1; P=0.030) with less endoplasmic reticulum Ca 2+ storage (cyclopiazonic acid-induced release AUC: Leu114Pro 17.5 vs. WT 46.8; P=0.008). TALK-1 Leu114Pro significantly blunted glucosestimulated insulin secretion compared to TALK-1 WT in mouse (52% decrease, P=0.039) and human (38% decrease, P=0.019) islets. These data suggest KCNK16 is a previously unreported gene for MODY.

Allosteric coupling between transmembrane segment 4 and the selectivity filter of TALK1 potassium channels regulates their gating by extracellular pH

“…The electrophysiological recording of TALK1-L114P mutants revealed a disruption of pH o sensitivity and a 15-fold increase in current density ( Fig. 3 , H and I ), in agreement with the previous study ( 29 ).…”

“…In conclusion, our study on the pH o -gating mechanism of TALK1 not only expands the understanding of how physiological stimuli regulate C-type gate in K2P channels but also provides a functional model to explain the complex behaviors of the chimeric K2P channels. This gating model could offer a crucial molecular basis for understanding the actions of WT and disease-causing mutant K2P channels ( 29 , 41 , 42 ).…”

“…1 B ) suggests that TALK1 may exhibit a different pH o gating mechanism than TASK2. Interestingly, a recent case report showed that a novel TALK1 mutant, L114P, causes maturity-onset diabetes of the young ( 29 ). TALK1 is abundantly expressed in the pancreatic β cells ( 9 , 30 ), and this gain-of-function L114P mutation was shown to inhibit glucose-stimulated insulin secretion ( 29 ).…”

Two-Pore-Domain Potassium (K2P-) Channels: Cardiac Expression Patterns and Disease-Specific Remodelling Processes

“…Together with K 2P 3.1 (TASK-1), K 2P 9.1 (TASK-3) contributes to peripheral and central respiratory regulation [ 195 ]. Therefore, these K 2P -channels are likely to constitute a molecular target of the respiratory stimulant doxapram [ 53 ].…”

pH-Dependence of Glucose-Dependent Activity of Beta Cell Networks in Acute Mouse Pancreatic Tissue Slice

“…Extracellular and intracellular [H + ] is typically in a nanomolar range, which is significantly lower than the concentrations of most other ions, small organic molecules, or even macromolecules like proteins and lipids. Isolated cells in culture can acutely tolerate a wider range of extracellular pH changes (pH [5][6][7][8][9][10][11]. Cells in intact tissues are more sensitive to pH deviations and the pH of the arterial blood is tightly regulated and maintained in a very narrow range between 7.36 and 7.…”