Ca2+ signaling of pancreatic acinar cells in malignant hyperthermia susceptibility.

Abstract

Background: Malignant hyperthermia susceptibility (MHS) and acute pancreatitis (AP) share a common cellular pathomechanism that is Ca²⁺-overload of the muscle fiber and the pancreatic acinar cell (PAC). In the muscle, gain-of-function mutations of the ryanodine receptor (RyR1) make the Ca²⁺-release mechanism hypersensitive to certain ligands, including Ca²⁺, volatile anaesthetics and succinylcholine, creating a medical emergency when the patient is exposed to these drugs. As RyR1 was shown to contribute to Ca²⁺-overload in PAC, we presumed that pancreata of MHS individuals are more prone to AP. Accordingly, a recent case study reported coincidence of MHS with recurrent AP, indicating a pathological link between the two diseases.

Methods: We tested if MHS poses a risk for AP in mice carrying the Y522S MHS mutation. Fluorescent Ca²⁺ imaging was performed in PACs. Conventional histopathological analysis and plazma amylase measurement was performed using a cerulein-induced pancreatitis mouse model.

Results: The intracellular Ca²⁺-signals of PACs from MHS mice were slightly bigger then in wild type when stimulated with 0.2 and 2 μM carbachol (cch) or with 1 and 5 mM bile acid (taurocholic acid). Store-operated-Ca²⁺-entry was also higher in PACs from MHS mice. Nevertheless, histopathological analysis and plasma amylase levels did not indicate more severe AP in MHS.

Conclusions: These results suggest that the Y522S RyR1 mutation alter the Ca²⁺-homeostasis in PACs, but not as much as to cause or aggravate AP.