De- and Resensitisation of Cardiac β-Adrenergic Receptor Signaling : A Modelling Approach

Abstract: Desensitisation is defined as a failure of a signaling pathway to respond to chronic or repeated stimulation. The β-adrenergic receptor signaling pathway of the healthy adult heart is known to desensitise, and then regain the sensitivity to stimulation if given enough time to rest between stimulations (resensitisation). The fetal heart does not desensitise, and in animal models of heart failure, a permanent desensitisation have been observed. No isolated element of the signaling pathway have yet been proven to be the sole modulator of the desensitisation behavior. Therefore a mathematical model of the signaling pathway has been constructed, minimized against theoretical desensitisation data and tested for resensitisation. The minimal models and the original model were capable of describing the theoretical de- and resensitisation of the pathway, and only one receptor type with three states was required in the minimal models, but one feedback from the kinases either to phosphorylation of the receptor or to breakdown of cAMP. The original model was also capable of describing experimental data of contraction force from chicken cardiac tissue. The cardiac tissue displays the peak behavior of the desensitisation when stimulated with ISO for ten minutes, and resensitises in less than 5 minutes.