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), i.e., "source" and by phosphodiesterases (PDEs) that hydrolyze it, i.e., "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 up-or down-regulate 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.

cAMP Signaling in Pathobiology of Alcohol Associated Liver Disease

“…As we discussed early in this review, regulation of cAMP signaling is fine-tuned by various enzymes in the cells. Recently, Getz et al suggested that cAMP signaling is also regulated by GIV/Girdin (Guanine nucleotide-binding (G) protein α subunit (Gα)-interacting vesicle-associated protein), the prototypical member of a family of modulators of trimeric GTPases, Guanine nucleotide Exchange Modulators (GEMs) [ 143 ]. The same group of investigators demonstrated that GIV mRNA is almost undetectable in normal human livers, but GIV mRNA expression increases with an increasing degree of liver fibrosis [ 135 ].…”

Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors

“…The loss of compartmentation in this context means that the system is no longer modifiable by the adrenoceptors. Counter-intuitively, the hydrolytic activity of PDEs can allow the persistence of high concentrations of cAMP within an effector microdomain through selective localization and source-to-sink fluxes [ 51 ]. The second and older notion of cAMP compartmentation is related to this, given that it was based on the idea of the ‘broadcast’ of cAMP.…”

GIV/Girdin, a Non-receptor Modulator for Gαi/s, Regulates Spatiotemporal Signaling during Sperm Capacitation and is Required for Male Fertility

“…As an activator of Gi and an inhibitor of Gs 14 using the same conserved GEM motif (Fig 7A ) GIV is known to tonically and robustly suppresses cAMP 15,50 , and by that token, it is expected to inhibit the cAMP surge. Because GIV-GEM was activated upon capacitation and remained active until the acrosome was shed (Fig 4F), we hypothesized that GIV's GEM function may be required for the prevention of a premature cAMP surge in the sperm head, and hence, premature acrosome exocytosis.…”