Non-canonical G protein signaling
Bernd Nürnberg1, Sandra Beer-Hammer1, Ellen Reisinger2
1Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, and ICePhA Mouse Clinic, University of Tübingen, Wilhelmstraße 56, D-72074 Tübingen, Germany.
Pharmacology & Therapeutics
|January 31, 2024
Summary
Activators of G protein signaling (AGS) proteins fine-tune cellular communication beyond classical pathways. This review explores their roles in health and disease, focusing on inhibitory G proteins (Gi) and future therapeutic potential.
Area of Science:
- Cellular Biology
- Molecular Signaling
- Biochemistry
Background:
- Classical G protein signaling involves receptors, G proteins, and effectors.
- Regulators like RGS and arrestins refine canonical pathways.
- Atypical signaling mechanisms and novel modulators, termed AGS proteins, expand this system.
Purpose of the Study:
- To review atypical G protein-dependent signaling mechanisms.
- To focus on inhibitory G proteins (Gi) in both canonical and non-canonical pathways.
- To discuss recent advancements, challenges, and therapeutic strategies.
Main Methods:
- Literature review and synthesis of current research on G protein signaling.
- Analysis of the roles of AGS proteins in cellular functions and diseases.
- Exploration of emerging therapeutic interventions targeting G protein pathways.
Main Results:
- AGS proteins modulate diverse cellular processes including development, division, transport, secretion, autophagy, and cell movement.
- Dysregulation of G protein signaling is implicated in major diseases like diabetes, cancer, and stroke.
- Non-canonical G protein pathways, particularly involving Gi, are increasingly recognized but poorly understood.
Conclusions:
- AGS proteins represent a critical layer of regulation in cellular communication with significant implications for health and disease.
- Further research is needed to elucidate the mechanisms and functions of non-canonical G protein signaling.
- Targeted pharmacological interventions hold promise for treating diseases associated with G protein pathway dysregulation.
Related Concept Videos
01:22Activation and Inactivation of G Proteins
7.2K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
7.2K
01:22Amplifying Signals via Enzymatic Cascade
8.5K
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
8.5K
01:15Amplifying Signals via Second Messengers
7.0K
Many receptor binding ligands are hydrophilic; they do not cross the cell membrane but bind to cell-surface receptors. Thus, their message must be relayed by second messengers present in the cell cytoplasm. There are several second messenger pathways, each with its own way of relaying information. For example, the G protein-coupled receptors can activate both phosphoinositol and cyclic AMP (cAMP) second messenger pathways. The phosphoinositol pathway is active when the receptor induces...
7.0K
01:11IP3/DAG Signaling Pathway
12.1K
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and...
12.1K
01:16Calmodulin-dependent Signaling
5.1K
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
5.1K
01:09GPCRs Regulate Adenylyl Cylase Activity
5.6K
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of...
5.6K