The Inhibition by Bitter Taste Receptors of the IP3 Receptor, and the Inclusion of a Bidirectional SERCA Pump

Abstract

The release and reuptake of Ca2+ from the cytosol to the sarcoplasmic reticulum (SR) of airway smooth muscle cells (ASMC) plays a vital role in regulating the frequency of Ca2+ oscillations, which in turn leads to the contraction or relaxation of the airways in the lungs. This thesis will be focused on investigating two recently discovered processes in ASMCs that have some part in how the oscillations behave. The first is concerned with how beta-adrenergic receptor agonists elevate cAMP in the ASMC and inhibit Ca2+ release from the IPR, resulting in a reduction in the frequency of Ca2+ oscillations and relaxation of the lungs, while the second is based around a recent experiment. This experiment compared the magnitude of lung contractile forces between wild type mice and transgenic mice, mice bred with higher expression of Ca2+ ATPase pumps (SERCA pumps) in the SR membrane (Ve). Results surprisingly showed the latter yielded a higher frequency of Ca2+ oscillations and greater lung contraction, which contradicts what previous mathematical models of ASMC predict. Our aim is to develop a mathematical model of ASMCs which is able to correctly predict these two physiological processes while conserving previously known behaviors of ASMCs. Also, we shall highlight the importance of using a bidirectional SERCA pump model by comparing a unidirectional and bidirectional version of a SERCA pump model and demonstrating that the latter succeeds in qualitatively replicating the above experimental result. We then investigate why the bidirectional pump is able to account for the short-comings of the unidirectional pump by computing the steady state concentrations of Ca2+ in the cytosol and SR and the key fluxes in the ASMC for both versions of our model. Our results indicate that it is the relative change in the fluxes in the respective models as Ve increases that determines whether frequency increases or decreases as an increasing function of Ve.