Piezo1 channel activation mimics high glucose as a stimulator of insulin release

Abstract

Glucose and hypotonicity induced cell swelling stimulate insulin release from pancreatic β-cells but the mechanisms are poorly understood. Recently, Piezo1 was identified as a mechanically-activated nonselective Ca2+ permeable cationic channel in a range of mammalian cells. As cell swelling induced insulin release could be through stimulation of Ca2+ permeable stretch activated channels, we hypothesised a role for Piezo1 in cell swelling induced insulin release. Two rat β-cell lines (INS-1 and BRIN-BD11) and freshly-isolated mouse pancreatic islets were studied. Intracellular Ca2+ measurements were performed using the fura-2 Ca2+ indicator dye and ionic current was recorded by whole cell patch-clamp. Piezo1 agonist Yoda1, a competitive antagonist of Yoda1 (Dooku1) and an inactive analogue of Yoda1 (2e) were used as chemical probes. Piezo1 mRNA and insulin secretion were measured by RT-PCR and ELISA respectively. Piezo1 mRNA was detected in both β-cell lines and mouse islets. Yoda1 evoked Ca2+ entry was inhibited by Yoda1 antagonist Dooku1 as well as other Piezo1 inhibitors gadolinium and ruthenium red, and not mimicked by 2e. Yoda1, but not 2e, stimulated Dooku1-sensitive insulin release from β-cells and pancreatic islets. Hypotonicity and high glucose increased intracellular Ca2+ and enhanced Yoda1 Ca2+ influx responses. Yoda1 and hypotonicity induced insulin release were significantly inhibited by Piezo1 specific siRNA. Pancreatic islets from mice with haploinsufficiency of Piezo1 released less insulin upon exposure to Yoda1. The data show that Piezo1 channel agonist induces insulin release from β-cell lines and mouse pancreatic islets suggesting a role for Piezo1 in cell swelling induced insulin release. Hence Piezo1 agonists have the potential to be used as enhancers of insulin release.

‘Resistance is futile?’ – paradoxical inhibitory effects of KATP channel closure in glucagon‐secreting α‐cells

“…When K ATP channel activity is reduced, the β-cells depolarize because the residual K + permeability is no longer sufficient to counteract the depolarizing influence of other membrane conductances that were previously too small to affect the membrane potential. The identity of the depolarizing background membrane conductance remains to be unequivocally identified; candidates include TRPM2 or Piezo1 (Yosida et al 2014;Deivasikamani et al 2019) and/or Cl − -permeable LRRC8 channels (also known as SWELL1 or VRAC) (Stuhlmann et al 2018).…”

“…2014; Deivasikamani et al . 2019) and/or Cl − ‐permeable LRRC8 channels (also known as SWELL1 or VRAC) (Stuhlmann et al . 2018).…”

Channelling the Force to Reprogram the Matrix: Mechanosensitive Ion Channels in Cardiac Fibroblasts

“…Together, studies elucidating the activation mechanisms of Pi-ezo1 suggest the channel is involved in integration of many forces that influence the tension of the plasma membrane and external environment surrounding the cell. Piezo1 can also be activated by the synthetic small molecule Yoda1 [216], which serves as a useful Piezo1 responds to a number of different types of mechanical stimuli in tissue culture, including lateral membrane tension [79,202,209], compression [210,211], osmotic swelling [212], and rhythmic mechanical stimulus [213], including 24-h cyclic stretch [214]. However, it should be noted that Piezo1 responsiveness to cyclic-stretch appears to be cell type-specific [34].…”

“…Piezo1 responds to a number of different types of mechanical stimuli in tissue culture, including lateral membrane tension [ 79 , 202 , 209 ], compression [ 210 , 211 ], osmotic swelling [ 212 ], and rhythmic mechanical stimulus [ 213 ], including 24-h cyclic stretch [ 214 ]. However, it should be noted that Piezo1 responsiveness to cyclic-stretch appears to be cell type-specific [ 34 ].…”

Manifestation of Pathological States of Numerous Diseases in the Largest Organ of the Human Body: (II) From Pancreatitis to Pancreatic Cancer Invasion, Formation of Stroma around the Primary Tumor in the Fascia, to Early Detection of Non-Coding microRNAs in Body Fluids and Development of Drugs to Treat Different Stages of Pancreatic Cancer

“…This figure was hand-painted by author PCWF. International Journal of Clinical Medicine branes of many cells, including cells of islets in the pancreas [25]. A Piezo1 channel (relevant to pancreatic cells) is schematically painted in Figure 2.…”