Receptor Signaling Pathways Quiz

Ligand-gated ion channels, G-protein coupled receptors, enzyme-linked receptors, and nuclear receptors.

The activated GPCR causes the exchange of GDP for GTP on the alpha subunit of the G protein.

The Ga-GTP subunit dissociates from the beta-gamma complex and activates adenylyl cyclase (AC).

Adenylyl cyclase converts ATP into cAMP, a second messenger.

cAMP binds to the regulatory subunit of PKA, causing them to dissociate from the catalytic subunits, activating PKA.

The catalytic subunits of PKA phosphorylate target proteins, triggering cellular responses.

The first G protein discovered contained an alpha subunit that could activate adenylyl cyclase (AC).

The discovery of the first G protein led to the realization that some hormones could inhibit adenylyl cyclase, a response also mediated by a G protein.

Gas stimulates AC, while Gai inhibits AC.

Beta-adrenoceptors, vasopressin receptor, and A2A/B adenosine receptors.

Alpha2 adrenoceptors, mu and delta opioid receptors, and A1/3 adenosine receptors.

Signaling via G proteins depends on the exchange of GDP for GTP.

Active alpha subunit has GTP bound. Hydrolysis of GTP leads to inactivation.

Cholera toxin (CTx) acts on the alpha subunit and causes ADP-ribosylation. This prevents hydrolysis of GTP, causing persistent activation of the alpha subunit.

In the colon, CTx causes activation of PKA-dependent Cl- channels and secretory diarrhea. AC -> cAMP -> CFTR -> diarrhea.

Pertussis toxin acts on the alphai subunit and locks it into an inactive configuration.

Pertussis toxin prevents activation by receptors and prevents its inhibitory control over AC/PKA.

Increased levels of cAMP and PKA. In airways, this leads to whooping cough.

G proteins containing alphaq11 subunits allow hormones/neurotransmitters to activate the amplifier enzyme phospholipids C (PLC).

Alphaq11-containing G proteins underlie the autonomic effects of acetylcholine (e.g., salivary secretion, bronchial smooth muscle contraction).

G proteins containing alphaq11 subunits mediate responses like smooth muscle contraction and allergies, which are due to increased internal Ca2+.

G proteins with the alphaq11 subunit activate phospholipid C. PLC cleaves PIP2 into IP3 and DAG. IP3 binds to receptors on the endoplasmic reticulum, causing the release of Ca2+ into the cytoplasm.

Activation of M3 receptors by alphaq11-containing G proteins causes bronchospasm.

Muscarinic receptors are metabotropic receptors coupled to Gq/Gi. Acetylcholine activates muscarinic receptors (metabotropic receptors). There are five subtypes.

M1, M3, and M5 are Gq-coupled stimulatory receptors.

M2 and M4 are Gi-coupled inhibitory receptors.

Salivary secretion and bronchial smooth muscle contraction are autonomic effects mediated by muscarinic receptors, through acetylcholine.

Gq proteins stimulate phospholipase C (PLC).

PLC cleaves PIP2 (a membrane phospholipid) into IP3 and DAG. It cleaves the polar head group of the phosphate.

IP3 is the water-soluble part of PIP2. It travels through the cytosol to stimulate calcium release from the ER.

Conversion of IP3 into IP2 inactivates IP3, halting the signal.

DAG remains in the hydrophobic part of the membrane, where it recruits protein kinase C (PKC).

Phospholipase Cß hydrolyses PIP2 into IP3 and DAG.

IP3 triggers Ca2+ release from the ER. DAG activates PKC in the membrane.

Binding of a hormone to a cell surface G protein-coupled receptor activates phospholipase Cß.

IP3 interacts with its receptor (IP3R) in the membrane of the ER, allowing the release of Ca2+ into the cytosol.

The SERCA Ca2+ pump transports Ca2+ back into the ER using ATP.

IP3 is a second messenger. It stimulates calcium release from the ER. It is hydrophilic, entering the cytoplasm. It binds to receptors on the ER and promotes release of stored Ca2+. It also promotes Ca2+ influx from extracellular fluid. The increase in intracellular free Ca2+ promotes cellular responses.

Calmodulin (CaM) is the most important calcium binding protein that mediates intracellular responses.

Calmodulin (CaM) modulated intracellular responses include: each CaM binds 4 Ca2+ ions to form the Ca2+-CaM complex.

The Ca2+-CaM complex activates PDE (the enzyme that degrades cAMP) and CaM kinases (CaMKs).

CaMKs phosphorylate serine and threonine residues on a number of substrate proteins. CaMKs are involved in smooth muscle contraction.

The alpha1 adrenoceptor is a Gq coupled protein receptor. It increases intracellular free Ca2+, activating CAMKs, leading to vasoconstriction.

DAG is a second messenger that affects cellular signaling. DAG evokes a cellular response by phosphorylating other proteins, with the most important being protein kinase C (PKC). DAG plays a role in receptor desensitization (similar to ß-ARK in GPCR signaling).

DAG is hydrophobic, remaining in the hydrophobic part of the plasma membrane.

The presence of DAG increases the activity of Ca2+ dependent protein kinase.

PKCs can potentiate the effects of IP3, enhancing downstream signaling.

PKC regulates cell shape, cell proliferation, and transcription factor activity.

The alpha1-adrenoceptor causes vasoconstriction via Gq-PLC-IP3-CaMK. It increases blood pressure.

The ß2-adrenoceptor causes relaxation of vascular smooth muscle (vasodilation) via Gs-cAMP-PKA. Blood pressure decreases.

Enzyme-linked receptors are a class of receptors that possess intrinsic enzymatic activity. These receptors include receptor guanylyl cyclases, receptor serine/threonine kinases, receptor tyrosine kinases (RTKs), tyrosine kinase-associated receptors, and receptor tyrosine phosphatases.

Receptor guanylyl cyclases contain two guanylyl cyclase domains, which convert GTP to cGMP. cGMP activates downstream kinases.

Binding of ANP induces a conformational change in the receptor, causing receptor dimerization and activation. The guanylyl cyclase activity of the receptor generates cGMP. Increased concentrations of cGMP activate other signaling molecules, determining the response. For example, atrial natriuretic peptide (ANP) relaxes vascular smooth muscle and dilates blood vessels (vasodilation).

The guanylyl cyclase activity of the receptor generates cGMP.

ANP signaling via guanylyl cyclase leads to vasodilation, causing relaxation of vascular smooth muscle and dilation of blood vessels.

Receptor serine/threonine kinases contain serine-threonine kinase domains, which phosphorylate target proteins (similar to PKA).

First messenger binds to receptor type II. Receptor type I then binds, forming a ternary complex with type II and the first messenger. Type II receptor phosphorylates type I, activating the Ser-Thr kinase activity of type I. Type I then phosphorylates target proteins (e.g., SMAD proteins). For example, TGFß mediated cell proliferation.

Receptor tyrosine kinases (RTKs) contain tyrosine kinase domains, which phosphorylate themselves and other proteins.

Binding of two molecules of insulin causes the receptor to dimerize. Receptors then use their cytoplasmic tyrosine kinase activity to phosphorylate each other at multiple tyrosine residues, creating “phosphotyrosine motifs”.

Phosphotyrosine motifs recruit intracellular signaling molecules, leading to the response.

Insulin mediated glucose uptake and storage in liver and muscles is an example of a cellular response mediated by receptor tyrosine kinases.

A signal molecule binds to and activates a receptor tyrosine kinase (RTK). The activated RTK undergoes dimerization and autophosphorylation at specific tyrosine residues.

An adaptor protein docks on a phosphotyrosine residue of the activated RTK, recruiting RAS-GEF.

RAS- GEF stimulates Ras to exchange its bound GDP for GTP, activating Ras.

The Ras protein, bound to GTP, is anchored to the plasma membrane via a covalently attached lipid group. It initiates the transmission of the signal to downstream pathways.

MAPKKK (Mitogen-activated protein kinase kinase kinase) is the first kinase in the cascade (e.g., RAF). It is activated by Ras-GTP and phosphorylates MAPKK. ATP->ADP.

MAPKK (Mitogen-activated protein kinase kinase) is the second kinase in the cascade (e.g., MEK). It is activated by MAPKKK and phosphorylates MAPK. ATP->ADP.

MAPK (Mitogen-activated protein kinase) is the third kinase in the cascade (e.g., ERK). It is activated by MAPKK and translocates to the nucleus to phosphorylate transcription factors, altering gene expression.

Tyrosine kinase-associated receptors do not contain kinase domains. They are associated non-covalently with the cytoplasmic domains.

Binding of the first messenger to the receptor induces a conformational change. This causes dimerization of the receptor. The dimerization causes activation of the associated Tyr kinases (e.g., JAK2). These kinases then phosphorylate tyrosine residues on both themselves and the receptor, creating “phosphotyrosine motifs” (like Tyr-kinase receptors). These motifs recruit intracellular signaling molecules, leading to the response (e.g., STAT proteins). For example, cytokine signaling pathway (IL-6 acute phase response).

Dimerization of the receptor activates the associated tyrosine kinases (e.g., JAK2).

Once activated, these kinases phosphorylate tyrosine residues on both themselves and the receptor, creating phosphotyrosine motifs.

Phosphotyrosine motifs recruit intracellular signaling molecules (e.g., STAT proteins), leading to cellular responses.

The cytokine signaling pathway (such as the IL-6 acute phase response) is an example of a signaling pathway mediated by tyrosine kinase-associated receptors.

Receptors contain tyrosine phosphatase domains and remove Tyr residues to dephosphorylate target proteins (e.g., Tyr residues created by Tyr kinase receptor signaling).

First messenger binding to the receptor induces a conformational change that activates the Tyr phosphatase activity of the receptor. Target proteins are dephosphorylated by Tyr phosphatase activity. This causes phosphorylation of downstream proteins (e.g., Lck and Fyn). For example, CD45 induces the maturation of lymphocytes via binding to this receptor.

The tyrosine phosphatase activity of the receptor dephosphorylates target proteins, modulating their activity.

Dephosphorylation of targets leads to the phosphorylation of downstream proteins (e.g., Lck and Fyn).

CD45 induces the maturation of lymphocytes by binding to this receptor.

GPCRs have 7 transmembrane helices, while RTKs have 1 transmembrane helix.

GPCRs have no enzymatic activity; they activate G proteins to relay the signal. RTKs have intrinsic catalytic activity that triggers phosphorylation.

GPCRs do not require dimerization. Ligand binding to RTKs can lead to dimerization of neighboring receptors.

GPCRs relay signals via secondary messengers (e.g., cAMP or IP3/DAG). RTKs relay signals without secondary messengers, using phosphorylation cascades.

GPCRs: seconds; RTKs: hours.

GPCRs can lead to protein phosphorylation or ion channel opening. RTKs primarily lead to phosphorylation cascades and activation of signaling pathways like Ras-GEF and PI 3-kinase.

Activated GPCR: G protein->adenylyl cyclase->cAMP->PKA. G protein->phospholipase C->IP3->Ca2+->calmodulin->CaM kinase. G protein->phospholipase C->diacylglycerol->PKC.

Activated RTK: PI 3-Kinase->phosphorylated inositol phospholipid->protein kinase 1->Akt kinase. Ras-GEF->Ras->MAPKKK->MAPKK->MAPK.