How pancreatic beta-cells discriminate long and short timescale cAMP signals

The translocation of catalytic protein kinase A (cPKA) in response to cyclic-adenosine mono-phosphate (cAMP) depends on the pattern of stimulus applied to the cell. Experiments with IBMX have shown that 1), sustained cAMP elevation is more effective than oscillations of cAMP at getting cPKA into the nucleus; and 2), cPKA enters the nucleus by diffusion. We constructed mathematical models of cAMP activation of cPKA and their diffusion in order to study nuclear translocation of cPKA, and conclude that hindered diffusion of cPKA through the nuclear membrane by a rapid-binding process, but not globally reduced diffusion, can explain the experimental data. Perturbation analysis suggests that normal physiological oscillations of glucose would not result in nuclear translocation, but chronically high glucose that produces extended calcium plateaus and/or chronic glucagonlike peptide-1 stimulation could result in elevated levels of nuclear cPKA.