Glucose‐ and arginine‐induced insulin secretion by human pancreatic β‐cells: the role of HERG K⁺channels in firing and release

Abstract

The human ether-a-go-go-related genes (herg) are expressed in tissues other than heart and brain where the HERG K(+) channels are known to regulate the repolarization of the heart action potential and the neuronal spike-frequency accommodation. We provide evidence that herg1 transcripts are present in human pancreatic islets that were used to study both insulin secretion and electrical activity with radioimmunoassay and single cell perforated patch-clamp techniques, respectively. Glucose- and arginine-induced islets insulin secretion data suggested a net increase of release under perfusion with antiarrhythmic drugs known to selectively block HERG channels. Indeed we could routinely isolate a K(+) current that was recognized as biophysically and pharmacologically similar to the HERG current. An analysis of the glucose- and arginine-induced electrical activity (several applications during 30 min) in terms of firing frequency and putative insulin release was done in control and in the presence of selective blockers of HERG channels: the firing frequency and the release increased by 32% and 77%, respectively. It is concluded that HERG channels have a crucial role in regulating insulin secretion and firing of human beta-cells. This raises the possibility that some genetically characterized hyperinsulinemic diseases of unknown origin might involve mutations in the HERG channels.

Arsenic trioxide induces the apoptosis of human breast cancer MCF-7 cells through activation of caspase-3 and inhibition of HERG channels

“…The finding of the association between hErG protein and integrins may provide new clues for further study. the hErG channel has also been related to tumor cell invasion and neoangiogenesis apart from its activity in cell proliferation (34)(35)(36). Shao et al found that inhibition of hErG protein expression reduced the invasiveness of gastric cancer cells (37).…”

Voltage-dependent K + channels in pancreatic beta cells: Role, regulation and potential as therapeutic targets

“…In this study Kvβ1.1, 2.1 and 2.2 were detected with high abundance, while Kvβ1.2, 1.3 and 3 were detected at lower levels. Additionally, one report showed the presence of the Kv-related human-ERG (hERG) K + channel (Table 1) in human islets [94]. Although these channels are thought to facilitate action potential repolarisation and perhaps modulate glucose-dependent bursting, the hERG antagonist WAY123 398 did not enhance glucose-stimulated insulin secretion in that study making the true role of these channels unclear.…”

Downregulation of the HERG (KCNH2) K+ channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation

“…Recently one form of the short-QT syndrome, a novel inherited arrhythmogenic disorder (Gussak et al, 2000), was identified as arising from a gain-offunction mutation in HERG (Brugada et al, 2004). HERG expression is not limited to cardiac tissue, with HERG current also regulating the excitability of neurones (Chiesa et al, 1997), jejunal smooth muscle (Farrelly et al, 2003) and pancreatic ␤-cells (Rosati et al, 2000). Furthermore, HERG is present in a variety of tumour cell lines of different histogenesis, as well as in primary human cancers (Pillozzi et al, 2002;Wang et al, 2002;Crociani et al, 2003;Lastraioli et al, 2004).…”