07: Receptors

Components needed to communicate signal transduction cascades

Chemical messengers and receptors

What type of messengers can reach intracellular receptors

Lipid-soluble messengers

Chemical messenger in the nervous system

Neurotransmitters

Chemical messenger in the endocrine system

Hormones

Chemical messenger in the immune system

Cytokines

Classes of endocrine secretion

• Endocrine

• Paracrine

• Autocrine

• Juxtacrine

Example of juxtacrine signaling

TCRs binding to MHC molecules

Results of a cell signaling pathway

• Survive

• Replicate

• Differentiate

• Die (apoptosis)

Intracellular membrane receptor function (most of the time)

Gene regulation

Common ligands for nuclear receptors

• Steroids

• Thyroid hormones

• Vit D

Primary response

The gene that is activated produces the protein responsible for the desired cellular response (early)

Secondary response

The primary response protein stimulates other genes that produce the protein responsible for the desired cellular response (delayed)

Physiological benefit of using secondary messengers

Allows a large response even if there is a low amount of primary messenger

Common secondary messengers

• cAMP

• cGMP

• Ca⁺⁺

• IP₃

• DAG

Common on/off switches in signalling pathways

• Phosphorylation/dephosphorylation

• GTP/GDP

Classes of cell surface receptors

• Ligand gated ion channels

• GPCR

• Catalytic/enzyme coupled receptors

• Nuclear receptors

Ligand gated ion channel mech

Ligand binding opens the one gate to allow ions to move according to electrochemical gradient (FAST)

GPCR mech

Ligand binding to receptor allows the attached G protein to swap GDP for GTP, and then the α subunit dissociates to activate another membrane bound protein

cAMP pathway

Ligand binds → GDP swaps for GTP → α subunit dissociates → activates adenylyl cyclase → ATP turned into cAMP → activates pkA

PIP₂/P₃ pathway

Ligand binds → GDP swaps for GTP → α subunit dissociates → activates PLC → breaks down PIP₂ to IP₃ and DAG → IP₃ signals for Ca⁺⁺ release from ER → activates PKC

• Also: DAG → activates PKC

Gs

Stimulator G-protein

Gi

Inhibitory G-protein

How does cholera interfere in a GPCR mediated cascade

Cholera makes ADP ribose bind to the α subunit, preventing it from being inactivated, causing prolonged activation of cAMP

Enzyme coupled receptor

Receptor that produces some sort of enzymatic activity either intrinsically or through direct association with an enzyme

Types of enzyme coupled receptors

• Receptor guanylyl cyclase

• Ser/Thr kinase

• RTK

• TK-associated

• RTPase

Receptor guanylyl cyclase funtion

Directly catalyzes the production of cGMP

Serine-threonine kinase function

Directly autophosphorylates serine or threonine residues

RTK function

Directly phosphorylates specific tyrosine residues on self or other ISPs

TK-associated receptor function

Recruits tyrosine kinase to relay signal

Receptor tyrosine phosphatase function

Activates ISPs via dephosphorylation

Receptor guanylyl cyclase

Receptor that converts GTP → cGMP, or otherwise directly associates with an enzyme that does so

Enzyme that breaks down cGMP

Phosphodieserase

Nitric Oxide signaling pathway (guanylyl cyclase example)

Ach release → causes cation release → activates NO synthetase → Arginine converted to NO → activates guanylyl cyclase → GTP to cGMP → smooth muscle relaxation → vasodilation

How do cGMP elevating drugs work

They inhibit cGMP phosphodiesterase, preventing the dissociation of the signal

RTK mechanism of action

Receptors that dimerize and transautophosphorylate when a ligand binds

What happens to RTKs after transautophosphorylation

Docking of other ISPs

What type of proteins can bind to activated RTKs

Those with SH₂ domains

Insulin signaling pathway (RTK example)

Insulin binds → RTK dimerizes and phosphorylates → IRS binds → IRS phosphorylates → activates PI₃K → converts PIP₂ to PIP₃ → activates PDK1 → activates Akt PK → upregulation of glucose transporters

Ras protein family

Family of monomeric GTPases that serve as molecular switch

TK-associated receptors

Have no intrinsic enzymatic activity, rather they recruit JAK

JAK-STAT pathway (TK-associated example)

Ligand (IFN) binds → TKAR phosphorylates → recruits JAK → JAK phosphorylates → recruits STAT → phosphorylates the STAT dimer → upregulates genes

Ser-Thr kinase receptor

Intrinsic catalytic activity resulting in phosphorylation after heterodimerization

Receptor tyrosine phosphatase

Catalytic receptor that activates proteins via dephosphorylation