Question: 

The immunosuppressant tacrolimus (FK506) has improved pancreas allograft survival compared to cyclosporin A (CsA), possibly due to reduced acute pancreatitis following ischemia-reperfusion injury. Ion permeabilities in zymogen granules (ZG) membranes, including a KCNQ1 K⁺ channel, promote hormone-stimulated enzyme secretion. We investigated whether a differential modulation of ZG and lysosomal ion permeabilities and enzyme secretion by CsA/FK506 contributes to pancreatitis.

Methods: 

Rat ZG and lysosomes were isolated by gradient centrifugation, ion permeabilities assayed by osmotic lysis, and single channel currents recorded in a planar lipid bilayer. Amylase release was measured in permeabilized acini and lysosomal cathepsin B release detected by immunoblotting.

Results: 

CsA (1–10mM), but not FK506, enhanced ZG osmotic lysis by selectively increasing K⁺ permeability up to 5-fold. ZG membrane K⁺ channels showed ~2-fold increased single channel open probability with CsA only. CsA selectively increased basal (~2-fold), but not cholecystokinin-octapeptide (1nM) -induced amylase secretion in K⁺ medium only. CsA (5mM), but not FK506, increased cathepsin B release from lysosomes.

Conclusions: 

CsA selectively opens the ZG K⁺ channel and induces cathepsin B release from lysosomes, which cause increased in situ lysis of ZG. This process may aggravate or fuel acute allograft pancreatitis and thus contribute to a loss of the transplanted pancreas.

Funding: Mukoviszidose e.V. (F 04/04) and DFG TH345/11-1.