G-proteins - structure, activation, function.

G-proteins, or guanine nucleotide-binding proteins, are a family of molecular switches that play an essential role in transducing extracellular signals into intracellular responses. They are involved in various physiological processes including vision, olfaction, neurotransmission, metabolism, and hormone signaling. G-proteins act as key intermediaries in signaling pathways initiated by G-protein-coupled receptors (GPCRs), the largest family of cell surface receptors.

Structure

G-proteins are typically heterotrimeric, consisting of three subunits:

• α-subunit – Binds GDP/GTP and has intrinsic GTPase activity. Determines the class of the G-protein (e.g., G_s, G_i, G_q, G_12/13).
• β-subunit – Forms a stable complex with the γ-subunit. Participates in signal modulation.
• γ-subunit – Anchors the G-protein to the membrane and stabilizes β-subunit.

• G protein structure.svg

  Structure of a G-protein heterotrimer

• G protein alpha subunit GDP GTP exchange.svg

  GDP-GTP exchange in Gα subunit

Activation

Activation of G-proteins is initiated by a ligand binding to a GPCR:

1. A signaling molecule (e.g., hormone, neurotransmitter) binds to a GPCR.
2. The receptor undergoes a conformational change and acts as a guanine nucleotide exchange factor (GEF).
3. The GDP bound to the Gα-subunit is exchanged for GTP.
4. GTP binding activates the Gα-subunit and causes its dissociation from the βγ-complex.
5. Both Gα-GTP and the βγ dimer can interact with downstream effectors (e.g., enzymes, ion channels).

The signal is terminated when the intrinsic GTPase activity of the Gα-subunit hydrolyzes GTP to GDP, inactivating the protein and allowing reassociation with βγ.

Types and functions

The α-subunit determines the class and function of the G-protein:

• G_s – Stimulates adenylyl cyclase, increasing cAMP production.

 * Example: β-adrenergic receptors

• G_i – Inhibits adenylyl cyclase, decreasing cAMP levels.

 * Example: α2-adrenergic receptors

• G_q – Activates phospholipase C → produces IP₃ and DAG → mobilizes calcium and activates protein kinase C.

 * Example: α1-adrenergic receptors

• G_12/13 – Regulates Rho GTPases involved in cytoskeletal rearrangement.

Downstream pathways

G-proteins mediate the activation of various intracellular signaling cascades:

• cAMP-PKA pathway (via G_s): activates protein kinase A, affecting metabolism and gene transcription.
• IP₃-DAG pathway (via G_q): releases calcium from the ER and activates protein kinase C.
• Ion channel modulation (via βγ): directly regulates K⁺ and Ca²⁺ channels in neurons and cardiomyocytes.

Clinical relevance

Malfunctions in G-protein signaling can lead to a range of diseases:

• Cholera – Cholera toxin modifies G_sα via ADP-ribosylation → constitutive activation → excessive cAMP → massive fluid loss.
• Pertussis – Pertussis toxin inhibits G_i → increased cAMP in immune cells.
• Pseudohypoparathyroidism – Genetic mutation in G_sα subunit impairs response to PTH despite normal hormone levels.
• Neoplasms – Activating mutations in G-proteins (e.g., GNAS gene) are linked to tumors such as pituitary adenomas and McCune-Albright syndrome.

GPCRs and G-proteins

G-protein-coupled receptors are characterized by seven transmembrane α-helices. They form the largest receptor family in the human genome. Each GPCR activates specific G-protein subtypes, enabling diverse physiological responses to similar signal types.

Examples of GPCR ligands:

• Adrenaline
• Dopamine
• Serotonin
• Histamine
• Light (rhodopsin in photoreceptors)

Regulatory proteins

Several accessory proteins regulate G-protein signaling:

• GTPase-activating proteins (GAPs) – Accelerate GTP hydrolysis (e.g., RGS proteins).
• Guanine nucleotide exchange factors (GEFs) – Facilitate GDP-GTP exchange.
• GDI (guanine nucleotide dissociation inhibitors) – Prevent spontaneous nucleotide exchange in some small G-proteins.

Small G-proteins

In addition to heterotrimeric G-proteins, there are **monomeric small GTPases** such as:

• Ras – involved in growth signaling
• Rho – regulates the actin cytoskeleton
• Rab – involved in vesicle trafficking

These are structurally different but share a common GDP/GTP switch mechanism.

Summary table

G-protein type	Effector enzyme	Second messenger	Effect
Gs	Adenylyl cyclase	↑ cAMP	Activates PKA
Gi	Adenylyl cyclase	↓ cAMP	Inhibits PKA
Gq	Phospholipase C	IP₃, DAG	↑ Ca2+, activates PKC

References

Related articles

• Signal transduction
• G-protein-coupled receptor
• Adenylyl cyclase
• Phospholipase C
• Protein kinase A
• Protein kinase C
• Second messengers

Literature

• ALBERTS, Bruce. Molecular Biology of the Cell. 6. edition. New York : Garland Science, 2015. 845–875 pp. ISBN 978-0-8153-3218-3.

• BERG, Jeremy M. – TYMOCZKO, John L.. Biochemistry. 8. edition. New York : W.H. Freeman, 2015. 322–340 pp. ISBN 978-1-4641-2610-7.