GPCR mediated control of calcium dynamics: A systems perspective

Abstract

G-protein coupled receptor (GPCR) mediated calcium (Ca2+)-signaling transduction remains crucial in designing drugs for various complex diseases including neurodegeneration, chronic heart failure as well as respiratory diseases. Although there are several reviews detailing various aspects of Ca2+ -signaling such as the role of IP3 receptors and Ca2+ -induced-Ca2+ -release, none of them provide an integrated view of the mathematical descriptions of GPCR signal transduction and investigations on dose-response curves. This article is the first study in reviewing the network structures underlying GPCR signal transduction that control downstream [ ]-oscillations. The central theme of this paper is to present the biochemical pathways, as well as molecular mechanisms underlying the GPCR-mediated Ca2+ -dynamics in order to facilitate a better understanding of how agonist concentration is encoded by Ca2+ -signaling. Moreover, we present the GPCR targeting drugs that are relevant for treating cardiac, respiratory, and neuro-diseases along with agonist concentration encoding of Ca2+ -response corresponding to Gαq, Gαs, and Gαi/o signaling. The current paper presents the ODE formulation for various models along with the detailed schematics of signaling networks. To provide a systems perspective, we present the network motifs that can provide readers an insight into the complex and intriguing science of agonist-mediated Ca2+ -dynamics. One of the features of this review is to pinpoint the interplay between positive and negative feedback loops that are involved in controlling intracellular [ ]-oscillations. Furthermore, we review several examples of dose-response curves obtained from [ ]-spiking for various GPCR pathways. This paper is expected to be useful for pharmacologists and computational biologists for designing clinical applications of GPCR targeting drugs through modulation of Ca2+ -dynamics.