Regulating cellular cyclic adenosine monophosphate: “Sources,” “sinks,” and now, “tunable valves”
Abstract
A number of hormones and growth factors stimulate target cells via the 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 ligand‐stimulated receptors that activate adenylate cyclases (ACs), that is, “source” and by phosphodiesterases (PDEs) that hydrolyze it, that is, “sinks.” Because it regulates various cellular functions, including cell growth and differentiation, gene transcription and protein expression, the cAMP signaling pathway has been exploited for the treatment of numerous human diseases. Reduction in cAMP is achieved by blocking “sources”; however, elevation in cAMP is achieved by either stimulating “source” or blocking “sinks.” Here we discuss an alternative paradigm for the regulation of cellular cAMP via GIV/Girdin, the prototypical member of a family of modulators of trimeric GTPases, Guanine nucleotide Exchange Modulators (GEMs). Cells upregulate or downregulate cellular levels of GIV‐GEM, which modulates cellular cAMP via spatiotemporal mechanisms distinct from the two most often targeted classes of cAMP modulators, “sources” and “sinks.” A network‐based compartmental model for the paradigm of GEM‐facilitated cAMP signaling has recently revealed that GEMs such as GIV serve much like a “tunable valve” that cells may employ to finetune cellular levels of cAMP. Because dysregulated signaling via GIV and other GEMs has been implicated in multiple disease states, GEMs constitute a hitherto untapped class of targets that could be exploited for modulating aberrant cAMP signaling in disease states.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Apr 23, 2020
- Source ID
- 10.1002/wsbm.1490
Entities
People
- Michael Getz
- Padmini Rangamani
- Pradipta Ghosh
Organizations
- Air Force Office of Scientific Research
- Army Research Office
- Division of Physics
- National Institutes of Health
- University of California, San Diego