Ion homeostasis and the functional roles of SERCA reactions in stimulus–secretion coupling of the pancreatic β-cell: A mathematical simulation

Abstract

The present paper concerns with ion homeostatic reactions in view of stimulus–secretion coupling of the β-cell, including Ca 2+ fluxes of the endoplasmatic reticulum (ER). A steady state of cytosolic sodium and potassium ion concentrations ([Na +] c and [K +] c, respectively), and of the membrane potential (Δ cϕ) can be attained only, if the flux through the electrogenic Na-K pump ( J NaK) is balanced electrically, and if J NaK is rather high (about 25% of total ATP consumption at 10 mM glucose). Metabolically caused changes of cellular pH are unlikely, because, on the one hand, CO 2 can rapidly leave the cell through cellular membranes, and because ATP cycling cannot produce nor consume protons. A slight decrease of pH c during cellular activity is caused mainly by an increased Ca-H exchange flux through the plasma membrane Ca 2+ pump ( J PMCA), which might be overcome, however, by H + transport into secretory granules. The present simulations show that the conductance of ATP-sensitive K + channels (K ATP) is highly susceptible to changes of [Mg 2+] c. As a physical link between the Ca 2+ filling state of the ER and the initiation of a depolarising, Ca 2+ release-activated current ( I CRAN), a metabolite (inositol 1,4,-diphosphate (IP 2)) of the inositol 1,4,5-triphosphate (IP 3) cycle is introduced. Sufficient ATP for insulin secretion is made available during glucose activation by [IP 2] inhibition of a parallel [ATP] c consuming flux through protein biosynthesis ( J Pbs). This leads to fast oscillations with a triphasic patterns of [Ca 2+] c oscillations. Slow oscillations are initiated by including a Ca 2+ leak current through highly uncoupled SERCA3 pumps. Both types of oscillations may superimpose yielding compound bursting and mixed oscillations of [Ca 2+] c.