Hydrophobic ligands Diffuse through cell membranes. Examples include steroid, thyroid hormones, retinoids, and vitamin D. Insoluble in water, require carrier proteins for transport Receptor binding Binds to intracellular receptors that are transcription regulators Intracellular receptors act as effectors. Nuclear receptor superfamily Orphan receptors: ligand unknown. PPARs: regulated by intracellular metabolites. Structural features of Nuclear reeptors They have a ligand-binding domain and a DNA-binding domain

Hydrophobic ligands

Steroid hormones, thyroid hormones, retinoids, and vitamin D

Insoluble in water, require carrier proteins for transport

Binds to intracellular receptors that are transcription regulators

effectors

A group of intracellular receptors that regulate gene expression

Receptors for which the ligand is unknown

regulated by intracellular metabolites.

They have a ligand-binding domain and a DNA-binding domain

consist of a single polypeptide chain that threads back and forth across the lipid bilayer 7 times, forming a cylindrical structure, often with a deep ligand-binding site at its center all use G proteins to relay the signal into the cell interior

Ligand binding activates GPCRs, which then activate G proteins. G protein association varies: pre-bound or post-activation. G proteins are composed of 3 protein subunits-a,B, and y. Inactive State: α subunit bound to GDP and the G protein is inactive. Activated GPCRs act as GEFs, promoting GTP binding. GTP binding activates Ga, leading to dissociation from Gβγ. Both Ga-GTP and Gβγ can then interact with enzymes and ion channels in the plasma membrane. a subunit is a GTPase Ga inactivates itself via GTP breaking. Target proteins or RGS proteins enhance GTP breaking

Ligand binding activates GPCRs, which then activate G proteins

GPCRs: largest cell-surface receptor family. 800 in humans, 1000 in mice for smell alone. Mediate:Most Responses to external and internal signals (hormones, neurotransmitters, local mediators). Half of all drugs target GPCRs or their pathways. Same signal, different GPCRs, different responses.

GPCRs, largest cell-surface receptor family. 800 in humans, 1000 in mice for smell alone.

Most Responses to external and internal signals (hormones, neurotransmitters, local mediators).

Half

Different responses can occur

A, b, y

Bound to GDP and the G protein is inactive.

GEFs, promoting GTP binding

It activates and dissociates from Gβγ.

Enzymes and ion channels in the plasma membrane.

A GTPase

By breaking down GTP

Target proteins or RGS proteins

G Proteins Directly Regulate lon Channels G Proteins Regulate the Production of Cyclic AMP G Proteins Signal Via Phospholipids

cAMP: synthesized from a ATP by adenylyl cyclase, degraded by phosphodiesterases. Signals activating Gs increase cAMP. Gsa activates adenylyl cyclase. Signals activating Gi decrease cAMP. Giα inhibits adenylyl cyclase.

synthesized from a ATP by adenylyl cyclase, degraded by phosphodiesterases

Signals activating Gs increase cAMP. Gsa activates adenylyl cyclase.

Signals activating Gi decrease cAMP. Giα inhibits adenylyl cyclase.

cAMP activates PKA. PKA phosphorylates specific serines or threonines target proteins including intracellular signaling proteins and effector proteins , altering their activity. Inactive PKA: 2 catalytic and 2 regulatory subunits bound. cAMP binding releases catalytic subunits.

Cyclic AMP activates PKA

specific serines or threonines on target proteins including intracellular signaling proteins and effector proteins , altering their activity.

consists of 2 catalytic and 2 regulatory subunits bound together

releases the catalytic subunits of PKA.

cAMP effects: rapid or delayed due to gene transcription. CRE: a short regulatory sequence in cAMP-activated genes. CREB binds to CRE. PKA phosphorylates CREB. Phosphorylated CREB recruits CBP, activating transcription.

CAMP-PKA

Rapid or delayed due to gene transcription

CRE

CREB

Breaks CREB

CBP

GPCRs activate PLCβ P(4,5)P2: minor component of inner half plasma membrane. Gq activates PLCβ, cleaving P(4,5)P2 into 2 second messengers IP3 and DAG. IP3 water-soluble molecule that leaves the plasma membrane and diffuses rapidly through the cytosol binds to ER receptors, releasing Ca2+. Ca2+ stored in the ER is released through the open channels, quickly raising concentration of Ca2+ in cytosol Increase in cytosolic Ca2+ promotes the signal by influncing activity of Ca2+-sensitive intracellular proteins

PLCβ

A minor component of the inner half of the plasma membrane

PLCβ, which cleaves P(4,5)P2 into IP3 and DAG.

water-soluble molecule that leaves the plasma membrane and diffuses through the cytosol binds to ER receptors, releasing Ca2+.

released through the open channels, quickly raising concentration of Ca2+ in cytosol

promotes the signal by influencing the activity of Ca2+-sensitive intracellular proteins.

* Ca2+ as a Signal: Many extracellular signals increase cytosolic Ca2+. * Ca2+ Roles: Triggers muscle contraction and secretion in many cells. * Ca2+ Distribution: Low in cytosol, high in extracellular space and ER/SR. * Ca2+ Influx: Transient channel opening leads to Ca2+ influx, increasing cytosolic concentration 10-20 fold. * PKC Activation: Diacylglycerol activates PKC, which is Ca2+-dependent. * PKC Translocation: IP3-induced Ca2+ rise triggers PKC translocation to the plasma membrane. * PKC Requirements: PKC activation needs Ca2+, diacylglycerol, and phosphatidylserine. * PKC Phosphorylation: Activated PKC phosphorylates cell-specific target proteins

Many intracellular signals increase cytosolic Ca2+.

Triggers muscle contraction and secretion in many cells

Low in cytosol, high in extracellular space and ER/SR

Transient channel opening leads to Ca2+ influx, increasing cytosolic concentration 10-20 fold.

Diacylglycerol activates PKC, which is Ca2+-dependent

IP3-induced Ca2+ rise triggers PKC translocation to the plasma membrane.

PKC activation needs Ca2+, diacylglycerol, and phosphatidylserine

Activated PKC phosphorylates cell-specific target proteins

Extracellular signals can induce large increases in second messengers like cAMP or Ca2+ (micromolar) from small changes in their own concentration (nanomolar). Second messengers act as allosteric effectors, amplifying the signal by activating numerous target proteins.

molecules that amplify signals within a cell.

induce large increases in second messengers like cAMP or Ca2+ from small changes in their own concentration.

Second messengers act as allosteric effectors, amplifying the signal by activating numerous target proteins.