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Regulating cellular cyclic adenosine monophosphate: "Sources," "sinks," and now, "tunable valves".

Michael Getz1, Padmini Rangamani2, Pradipta Ghosh3,4,5

  • 1Chemical Engineering Graduate Program, University of California San Diego, La Jolla, California, USA.

Wiley Interdisciplinary Reviews. Systems Biology and Medicine
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Summary

Guanine nucleotide Exchange Modulators (GEMs), like GIV/Girdin, offer a novel way to control cellular cyclic adenosine monophosphate (cAMP) levels. This tunable valve mechanism presents new therapeutic targets for diseases linked to aberrant cAMP signaling.

Keywords:
cyclic AMPguanine exchange modulators (GEMs)noncanonicalphosphodiesterasestrimeric GTPases

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Area of Science:

  • Biological Mechanisms
  • Cell Signaling
  • Mechanistic Models

Background:

  • Cellular functions are regulated by hormones and growth factors acting through second messenger pathways.
  • Cyclic adenosine monophosphate (cAMP) is a key second messenger controlling cell growth, differentiation, and gene expression.
  • Current strategies to modulate cAMP target its production ('sources') or degradation ('sinks').

Purpose of the Study:

  • To introduce a novel paradigm for regulating cellular cAMP levels via Guanine nucleotide Exchange Modulators (GEMs).
  • To explore the role of GIV/Girdin as a prototypical GEM in modulating cAMP.
  • To highlight GEMs as a new class of therapeutic targets for diseases involving dysregulated cAMP signaling.

Main Methods:

  • Discussion of an alternative paradigm for cAMP regulation.
  • Introduction of GIV/Girdin as a modulator of trimeric GTPases (GEMs).
  • Reference to a network-based compartmental model analyzing GEM-facilitated cAMP signaling.

Main Results:

  • GEMs, such as GIV, act as 'tunable valves' to fine-tune cellular cAMP levels.
  • GEM-mediated cAMP regulation operates via spatiotemporal mechanisms distinct from traditional 'sources' and 'sinks'.
  • Dysregulated signaling of GIV and other GEMs is implicated in various disease states.

Conclusions:

  • GEMs represent a previously untapped class of targets for modulating cAMP signaling.
  • Targeting GEMs offers a new therapeutic strategy for diseases characterized by aberrant cAMP levels.
  • GIV/Girdin and related GEMs provide a novel mechanism for cellular cAMP homeostasis.