Signal Transduction and G Protein–Coupled Receptors

Comprehensive vocabulary flashcards covering the principles of signal transduction, intracellular switches, second messengers, and G protein-coupled receptor mechanisms based on Lecture 17.

First Messengers

Extracellular signaling molecules (ligands) that are synthesized, packaged into secretory vesicles, and released by signaling cells, or exogenously derived molecules from the environment that bind cellular receptors.

Endocrine Signaling

A form of cell signaling in which hormones are synthesized and secreted into the bloodstream by specialized endocrine cells, traveling through the circulatory system to act on distant target cells.

Paracrine Signaling

Cell-to-cell signaling where released signaling molecules diffuse locally through extracellular fluid to act only on nearby adjacent target cells expressing the appropriate receptors.

Neuronal Signaling

A specialized subtype of paracrine signaling where electrical impulses are conducted along an axon to a synapse, releasing neurotransmitters that diffuse across the synaptic cleft to bind receptors on a target cell.

Autocrine Signaling

A signaling mode in which a cell secretes molecules, such as growth factors, that bind to and activate surface receptors on the very same cell that released them.

Juxtacrine Signaling

Intercellular communication occurring either via direct membrane-to-membrane contact of plasma-membrane-attached proteins or through cytoplasmic conduits called gap junctions.

Protein Kinase

An enzyme that transfers a terminal phosphate group from ATP to the hydroxyl group of a specific serine, threonine, or tyrosine residue contained within a target protein recognition motif.

Protein Phosphatase

An enzyme that removes phosphate groups from phosphorylated target proteins via hydrolysis, restoring the unphosphorylated serine, threonine, or tyrosine residue.

Guanine Nucleotide Exchange Factor (GEF)

An activator regulatory protein that promotes the transition of a G protein from the inactive to active state by catalyzing the dissociation of bound GDP to allow replacement by GTP.

GTPase-Activating Protein (GAP)

An inactivator protein that, together with regulators of G protein signaling (RGSs), accelerates the intrinsic GTPase activity of a G protein, speeding up GTP hydrolysis to GDP and inorganic phosphate ($P_i$).

Guanine Nucleotide-Dissociation Inhibitor (GDI)

A regulatory protein that prevents G protein activation by inhibiting the release of bound GDP, thereby maintaining the G protein in its inactive off conformation.

Switch I and Switch II

Flexible loop domains of monomeric G proteins (such as Ras) that bind the terminal $\gamma$ phosphate of GTP via conserved Thr-35 and Gly-60 residues to adopt the active conformation.

Second Messengers

Small, soluble intracellular signaling molecules (e.g., cAMP, cGMP, $IP_3$, DAG, $Ca^{2+}$) synthesized or released in response to first messenger binding that diffuse through the cytosol to regulate specific target proteins.

Inositol 1,4,5-Trisphosphate ($IP_3$)

A soluble second messenger produced from $PIP_2$ by the enzyme phospholipase C that binds to and opens calcium channels in the endoplasmic reticulum membrane.

1,2-Diacylglycerol (DAG)

A membrane-bound lipid second messenger generated alongside $IP_3$ by phospholipase C that acts synergistically with $Ca^{2+}$ to activate protein kinase C (PKC).

Nitric Oxide (NO)

A gaseous, highly reactive second messenger produced by nitric oxide synthase that diffuses across membranes, lasts only a few seconds, and mediates autocrine and paracrine signaling.

Receptor Agonist

A synthetic chemical analog that mimics a natural hormone by binding to and activating its receptor to elicit a normal cellular response.

Receptor Antagonist

A synthetic analog that binds to a receptor's ligand-binding site without activating it, preventing the natural hormone from binding and blocking downstream physiological activity.

Isoproterenol

A synthetic agonist of bronchial smooth muscle $\beta_2$ adrenergic receptors that binds with approximately 10-fold higher affinity ($10\times$ lower $K_d$) than epinephrine to relax airways in respiratory diseases.

Alprenolol

A synthetic beta-blocker (antagonist) that binds cardiac muscle $\beta_1$-adrenergic receptors to block epinephrine-mediated acceleration of heart contractions, used for cardiac arrhythmias and angina.

G Protein–Coupled Receptor (GPCR)

The largest superfamily of cell-surface receptor proteins in animal genomes, characterized by seven $\alpha$-helical transmembrane domains, four extracellular segments, and four cytosolic segments.

Heterotrimeric G Protein

A membrane-anchored GTP-binding protein complex made of $\alpha$, $\beta$, and $\gamma$ subunits tethered by lipid modifications that dissociates into active $G_\alpha\cdot\text{GTP}$ and $G_{\beta\gamma}$ following GPCR activation.

Muscarinic Acetylcholine Receptor

A heart muscle GPCR that upon acetylcholine binding activates a $G_{\alpha i}$ protein, allowing dissociated $G_{\beta\gamma}$ subunits to directly bind and open $K^+$ channels, hyperpolarizing the cell and lowering heart rate.

Adenylyl Cyclase (AC)

A membrane-bound effector enzyme containing two integral membrane domains (each with six transmembrane $\alpha$ helices) and two cytosolic catalytic domains that convert ATP into the second messenger cAMP.

cAMP Phosphodiesterase (PDE)

An enzyme that terminates cAMP signaling by hydrolyzing the cyclic phosphodiester bond of cAMP, converting it to non-signaling AMP.

$G_{\alpha s}$ and $G_{\alpha i}$

Opposing regulatory alpha subunits of heterotrimeric G proteins; $G_{\alpha s}\cdot\text{GTP}$ stimulates adenylyl cyclase to increase cAMP levels, whereas $G_{\alpha i}\cdot\text{GTP}$ inhibits adenylyl cyclase activity.

Protein Kinase A (PKA)

A cAMP-dependent tetrameric enzyme consisting of two regulatory (R) and two catalytic (C) subunits; binding of four cAMP molecules to the R subunits releases active, free catalytic subunits.

Glycogen Synthase (GS)

An enzyme that incorporates UDP-glucose into glycogen; it is inactivated via phosphorylation by PKA and activated via dephosphorylation by phosphoprotein phosphatase (PP).

Glycogen Phosphorylase Kinase (GPK)

A cascade kinase that is phosphorylated and activated by PKA, which then phosphorylates and activates glycogen phosphorylase to promote glycogen breakdown.

Glycogen Phosphorylase (GP)

The terminal enzyme in glycogenolysis that catalyzes the phosphorolysis of glycogen to produce glucose-1-phosphate; it is activated by phosphorylation by GPK.

Phosphoprotein Phosphatase (PP)

A phosphatase that reverses PKA effects by activating glycogen synthase (GS) and inactivating GPK and GP; it is inhibited by a PKA-phosphorylated inhibitor protein (IP).

Signal Amplification

A feature of signal transduction pathways where the binding of a single ligand (e.g., $10^{-10}\,\text{M}$ epinephrine) triggers multiple enzymatic and catalytic steps to produce high concentrations of downstream products.

CREB (cAMP Response Element-Binding Protein)

A nuclear transcription factor phosphorylated by translocated PKA catalytic subunits that recruits CBP/P300 and binds cAMP response elements (CRE) to activate transcription of gluconeogenic genes.

GPCR Desensitization

A mechanism of terminating signaling where GPCR kinases (GRKs) phosphorylate cytosolic loops of active receptors, recruiting $\beta$-arrestin to block further G protein activation and initiate receptor endocytosis.

$\beta$-Arrestin

A cytosolic adaptor protein that binds phosphorylated GPCRs to block G protein coupling, recruit AP2 and clathrin for receptor endocytosis, and act as a scaffold for MAP kinase and Jun kinase signaling cascades.