Sodium/hydrogen exchanger NHA2 is critical for insulin secretion in β-cells

Abstract

NHA2 is a sodium/hydrogen exchanger with unknown physiological function. Here we show that NHA2 is present in rodent and human β-cells, as well as β-cell lines. In vivo, two different strains of NHA2-deficient mice displayed a pathological glucose tolerance with impaired insulin secretion but normal peripheral insulin sensitivity. In vitro, islets of NHA2-deficient and heterozygous mice, NHA2-depleted Min6 cells, or islets treated with an NHA2 inhibitor exhibited reduced sulfonylurea- and secretagogue-induced insulin secretion. The secretory deficit could be rescued by overexpression of a wild-type, but not a functionally dead, NHA2 transporter. NHA2 deficiency did not affect insulin synthesis or maturation and had no impact on basal or glucose-induced intracellular Ca 2+ homeostasis in islets. Subcellular fractionation and imaging studies demonstrated that NHA2 resides in transferrin-positive endosomes and synaptic-like microvesicles but not in insulin-containing large dense core vesicles in β-cells. Loss of NHA2 inhibited clathrin-dependent, but not clathrin-independent, endocytosis in Min6 and primary β-cells, suggesting defective endo–exocytosis coupling as the underlying mechanism for the secretory deficit. Collectively, our in vitro and in vivo studies reveal the sodium/proton exchanger NHA2 as a critical player for insulin secretion in the β-cell. In addition, our study sheds light on the biological function of a member of this recently cloned family of transporters.

Traditional and emerging roles for the SLC9 Na+/H+ exchangers

“…in native osteoclasts) or exogenously in transfected mammalian cells. In addition, data from our laboratory indicate both at a functional and biochemical level that NHA2 is also present in endosomes [38,66].…”

“…In support of this, overexpression or loss of intracellular NHEs alters organellar pH [113,35,130,80]. This concept is however challenged by studies where knock-down or loss of individual organelle-specific NHEs had no effect on pH [38,147,52]. Although redundance may theoretically explain the latter finding, clear biological effects were nevertheless observed, questioning the sole role of organellar NHEs in endomembrane pH regulation [52,38].…”

“…This concept is however challenged by studies where knock-down or loss of individual organelle-specific NHEs had no effect on pH [38,147,52]. Although redundance may theoretically explain the latter finding, clear biological effects were nevertheless observed, questioning the sole role of organellar NHEs in endomembrane pH regulation [52,38]. Since NHEs exchange cations for protons, they not only affect intraluminal H + concentration but also the concentration of Na + and K + , depending on ion selectivity.…”

“…A recent study looked at the role of NHA2 in the endocrine pancreas in detail [38]. NHA2 was found to be expressed both in 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 found to reside in endosomes and synaptic-like microvesicles in β-cells.…”

Dynamin 2 regulates biphasic insulin secretion and plasma glucose homeostasis

“…It underscores the crucial role of dynamin 2 in biphasic insulin secretion and suggests endocytic control of hormone secretion in vivo. Along the same line, two recent studies provided extra evidence that aberrant endocytic trafficking in β cells may contribute to the pathophysiology of diabetes (79,80).…”