Na+ current properties in islet α- and β-cells reflect cell-specific Scn3a and Scn9a expression

Key points α‐ and β‐cells express both Nav1.3 and Nav1.7 Na+ channels but in different relative amounts. The differential expression explains the different properties of Na+ currents in α‐ and β‐cells. Nav1.3 is the functionally important Na+ channel α subunit in both α‐ and β‐cells. Islet Nav1.7 channels are locked in an inactive state due to an islet cell‐specific factor. Mouse pancreatic β‐ and α‐cells are equipped with voltage‐gated Na+ currents that inactivate over widely different membrane potentials (half‐maximal inactivation (V0.5) at −100 mV and −50 mV in β‐ and α‐cells, respectively). Single‐cell PCR analyses show that both α‐ and β‐cells have Nav1.3 (Scn3) and Nav1.7 (Scn9a) α subunits, but their relative proportions differ: β‐cells principally express Nav1.7 and α‐cells Nav1.3. In α‐cells, genetically ablating Scn3a reduces the Na+ current by 80%. In β‐cells, knockout of Scn9a lowers the Na+ current by >85%, unveiling a small Scn3a‐dependent component. Glucagon and insulin secretion are inhibited in Scn3a−/− islets but unaffected in Scn9a‐deficient islets. Thus, Nav1.3 is the functionally important Na+ channel α subunit in both α‐ and β‐cells because Nav1.7 is largely inactive at physiological membrane potentials due to its unusually negative voltage dependence of inactivation. Interestingly, the Nav1.7 sequence in brain and islets is identical and yet the V0.5 for inactivation is >30 mV more negative in β‐cells. This may indicate the presence of an intracellular factor that modulates the voltage dependence of inactivation

Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin B receptor

PubMedID: 19755480Context: The neurokinin B (NKB) receptor, encoded by TACR3, is widely expressed within the central nervous system, including hypothalamic nuclei involved in regulating GnRH release. We have recently reported two mutations in transmembrane segments of the receptor and a missense mutation in NKB in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH). Patients and Methods:Wesequenced the TACR3 gene in a family in which three siblings had nIHH. The novel mutant receptor thus identified was studied in a heterologous expression system using calcium flux as the functional readout. Results: All affected siblingswerehomozygousfor the His148Leu mutation, in the first extracellular loop of theNKB receptor. The His148Leu mutant receptor exhibited profoundly impaired signaling in response to NKB (EC50 = 3 ± 0.1 nM and >5 µM for wild-type and His148Leu, respectively). The location of the mutation in an extracellular part of the receptor led us also to test whether senktide, a synthetic NKB analog, may retain ability to stimulate the mutant receptor. However, the signaling activity of the His148Leu receptor in response to senktide was also severely impaired (EC50 = 1 ± 1 nM for wild-type and no significant response of His148Leu to 10 µM). Conclusions: Homozygosity for the TACR3 His148Leu mutation leads to failure of sexual maturation in humans, whereas signaling by the mutant receptor in vitro in response to either NKB or senktide is severely impaired. These observations further strengthen the link between NKB, the NKB receptor, and regulation of human reproductive function. Copyright © 2009 by The Endocrine Society

Generation of L Cells in Mouse and Human Small Intestine Organoids

Nephrolog

Targeting development of incretin-producing cells increases insulin secretion

Nephrolog

A cross-platform approach identifies genetic regulators of human metabolism and health.

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10-10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights