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A computational investigation on spatial and temporal dynamics of cAMP

  • Author(s): Getz, Michael
  • Advisor(s): Rangamani, Padmini
  • Ghosh, Pradipta
  • et al.

Signaling networks are spatiotemporally organized in order to sense diverse inputs from the extracellular space, process information, and carry out specific cellular tasks. Various hormones and growth factors stimulate target cells through second messenger pathways, which in turn regulate cellular phenotypes. Cyclic adenosine monophosphate (cAMP) is a ubiquitous second messenger that facilitates numerous signal transduction pathways; its production in cells is tightly balanced by activation of adenylate cyclases (ACs), i.e. ``sources," and phosphodiesterases (PDEs) that hydrolyze it, i.e. ``sinks." Since cAMP regulates various cellular functions, including cell growth/differentiation, gene transcription/protein expression, and hormone secretion, this has been exploited for the treatment of numerous human diseases. Here, we discuss two methods of information encoding in the cAMP pathway-- regulation of cellular cAMP through GIV/Girdin in cancers and spatiotemporal control of sources and sinks of cAMP in pancreatic $\beta$ cells. In the first part, we describe a network-based compartmental model of non-canonical cAMP signaling which reveals that Guanine nucleotide Exchange Modulators (GEMs), such as GIV/Girdin, serve as ``tunable valves" that cells may employ to finetune cellular levels of cAMP. In the second part, we model the spatiotemporal regulation of Ca$^{2+}$-cAMP in pancreatic $\beta$ cells. Ca$^{2+}$, cAMP, and Protein Kinase A (PKA) exist in an oscillatory circuit characterized by a high degree of feedback allowing specific controls based on oscillation frequencies. We describe a novel mode of regulation within this circuit involving a spatial dependence of the relative phase between cAMP, PKA, and Ca$^{2+}$. We show nanodomain clustering of Ca$^{2+}$-sensitive adenylyl cyclases drives precisely in-phase cAMP oscillations with Ca$^{2+}$ within the membrane nanodomain, whereas Ca$^{2+}$-sensitive phosphodiesterases maintain out-of-phase oscillations within the general plasma membrane outside of the nanodomain, providing a striking example and novel mechanism of cAMP compartmentation. Disruption of this precise in-phase relationship perturbs Ca$^{2+}$ oscillations, suggesting that the relative phase within an oscillatory circuit can encode specific functional information. Thus, mathematical modeling of spatiotemporal dynamics of second messengers gives insight into their cellular function.

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