Adenylyl Cyclase - cAMP Pathway || Gs and Gi Protein Pathway

Summary

The video explains how Gs- and Gi-coupled receptors regulate the adenylyl cyclase–cAMP pathway. Gs generally increases cellular activity, while Gi generally decreases it, largely by stimulating or inhibiting adenylyl cyclase.

Gs pathway: increasing cAMP signaling

1. Resting state: The Gs protein’s α, β, and γ subunits are together, and the α subunit is bound to GDP.
2. Receptor activation: A ligand binds a Gs-coupled receptor, prompting GDP to leave the α subunit and GTP to bind.
3. Subunit separation: The GTP-bound αs subunit separates from the βγ complex and moves along the membrane.
4. Adenylyl cyclase activation: αs activates the membrane-bound enzyme adenylyl cyclase.
5. cAMP production: Adenylyl cyclase converts ATP into cyclic AMP (cAMP), raising intracellular cAMP levels.
6. PKA activation: cAMP activates protein kinase A (PKA).
7. Cellular effects: PKA phosphorylates target proteins—including transporters, metabolic enzymes, transcription factors, and structural proteins—changing their activity and influencing cellular functions.

Examples:

• In cardiac cells, adrenaline activates β1 receptors and the pathway, ultimately increasing myocardial contractility.
• In liver cells, glucagon activates Gs-coupled receptors, promoting phosphorylation of enzymes involved in glycogen breakdown and helping release glucose.

How the Gs signal is terminated

The video describes several mechanisms that switch off the response:

• GTP hydrolysis: The α subunit’s GTPase activity converts GTP to GDP and inorganic phosphate. The inactive α subunit leaves adenylyl cyclase and reunites with βγ.
• cAMP breakdown: Phosphodiesterase converts cAMP into AMP, reducing PKA activation.
• Dephosphorylation: Protein phosphatases remove phosphate groups from target proteins, reversing their phosphorylation-related effects.

Gi pathway: reducing cAMP signaling

Gi proteins have αi, β, and γ subunits and undergo a similar receptor-driven GDP-to-GTP exchange and subunit separation. The αi subunit inhibits adenylyl cyclase, reducing cAMP production and downstream signaling. The video presents this as generally decreasing cellular activity.

Examples:

• In the sinoatrial (SA) node, acetylcholine activates M2 receptors, inhibiting adenylyl cyclase and reducing impulse generation and heart rate.
• In pancreatic β cells, adrenaline activates α2-adrenergic receptors, inhibiting the pathway and decreasing insulin release.

Coordinating opposing signals

A cell can receive both Gs- and Gi-mediated signals, allowing the same function to be regulated in opposite directions. The video uses cardiac activity as an example: sympathetic signaling through β1 receptors raises cAMP and contractility, while parasympathetic acetylcholine signaling through M2 receptors lowers cAMP and cardiac activity. The net effect depends on which input predominates.

Subtitle inconsistency: One passage identifies the cardiac Gi-coupled receptor as M1, but the later explanation identifies it as M2.

Speakers and sources featured

• Speaker: A single narrator presenting the educational explanation.
• Source: The video’s educational material is attributed to the Nonstop Neuron channel.