cell signalling

G Protein Coupled Receptors (GPCRs)

Definition: GPCRs are a large family of cell surface receptors that play a key role in transmitting signals from outside the cell to its interior.
Importance in Medicine: GPCRs are commonly targeted by a variety of drugs due to their significant involvement in various physiological processes and conditions, including cancer.

Intercellular vs Intracellular Signaling: Intercellular signaling refers to communication between different cells, while intracellular signaling refers to signals exchanged within a single cell.
Signal Transduction: The process where an external signal (ligand) binds to a receptor, leading to a chain of biochemical reactions inside the cell which cause a specific cellular response.
Ligand: A molecule (often a protein) that binds specifically to a receptor, triggering a signaling cascade.
Receptors: Cell surface proteins that bind ligands and initiate signal transduction pathways.
Second Messengers: Intracellular molecules that amplify the signal and lead to a cellular response. Examples include cyclic AMP (cAMP).

Endocrine Signaling: Involves hormone signaling where hormones are released into the bloodstream and affect distant cells.
Paracrine Signaling: Involves signaling molecules that act on neighboring cells.
Autocrine Signaling: Occurs when signaling molecules affect the same cell that secretes them, potentially leading to uncontrolled growth and transformation into cancer cells.
Contact-Dependent Signaling: Requires direct interaction between neighboring cells, commonly seen in the nervous system.
Synaptic Signaling: Neurotransmitters are released from neurons into the synaptic cleft to communicate with target cells.
Gap Junction Signaling: Allows for direct communication between adjacent cells through channels.

Structure of G Proteins: Composed of three subunits – alpha, beta, and gamma. They exist in an inactive GDP-bound state and become active when bound to GTP.
Activation Cycle: Binding of ligand to a GPCR induces a conformational change, activating the associated G protein by exchanging GDP for GTP on the alpha subunit.
Functional Consequences: The activated G protein can separate into alpha-GTP and beta-gamma subunits, which can initiate various downstream signaling pathways, such as activating enzymes like adenyl cyclase to produce cAMP.

cAMP as a Second Messenger: Produced by adenyl cyclase, it activates protein kinase A (PKA) to regulate various cellular functions through phosphorylation of target proteins.
Role of Phosphodiesterases (PDEs): Enzymes that degrade cAMP into AMP, effectively shutting down the signaling pathway, illustrating the importance of regulation in signaling.

Inositol Phosphate Pathway: Activated by G proteins (specifically alpha-q), leading to the production of inositol trisphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol (PIP2).
Function of IP3: Triggers the release of calcium ions from the endoplasmic reticulum, serving as another secondary messenger.
Role of DAG: Activates protein kinase C (PKC), which phosphorylates various targets leading to diverse cellular responses.

Mechanism of Action: Involved in the regulation of blood vessels; nitric oxide (NO) is produced by nitric oxide synthase in endothelial cells in response to stimuli (like acetylcholine).
Role of cGMP: NO diffuses into smooth muscle cells and activates guanylate cyclase, leading to the production of cGMP, which causes relaxation of smooth muscle and reduced blood pressure.
Characteristics: NO is a short-lived signaling molecule, quickly oxidized to stable forms, limiting its signaling duration.

Function: Nuclear receptors are transcription factors that regulate gene expression in response to steroid hormones and other lipophilic signaling molecules.
Activation Mechanism: Upon ligand binding, these receptors typically translocate to the nucleus and bind to specific DNA sequences, affecting transcription.
Examples of Ligands: Include steroids (like testosterone and estrogen), retinoic acid, vitamin D, and thyroid hormones.
Receptor Characteristics: Composed of distinct functional domains, including ligand-binding and DNA-binding domains, allowing for diverse interactions and regulatory mechanisms.