Cell Signaling

Ligand-Gated Ion Channel Receptors

Integral membrane proteins acting as receptor-channels. Acetylcholine binds and activates entry of Na+ making it more positive in the cell. Also called Ionotropic Receptors

G Protein-Coupled Receptors (GPCRs)

Has a intermediary step to activate/inactive a sperate membrane: G-Protein (coupled with gamma, beta, alpha)

Largest Family of Receptor

G Protein-Coupled Receptors (GPCRs).

G Protein as a heterotimer

A protein complex that consists of three subunits (alpha, beta, and gamma)

when GDP is bound to alpha = inactive
GTP is bound to alpha = active

What happens when G-protein is activated?

Moves alpha away to E1 to activate an effector protein, triggering a cellular response.

E1 Complex can consist of what

Adenylyl Cyclase, Phosphodieterase, Phospholipases

Catalytic Receptors

Integral membrane proteins with enzymatic activity or part of enzyme complexes; include guanylyl cyclases and receptor tyrosine kinases.

Nuclear Receptors

Intracellular receptors in the cytoplasm or nucleus that act as ligand-activated transcription factors, binding to hormone response elements on DNA.

Second Messengers

Intracellular molecules that amplify signals, including cAMP, cGMP, IP3, DAG, Arachidonic Acid, and Ca2+.

cAMP

Cyclic adenosine monophosphate; formed by adenylyl cyclase; activates protein kinase A (PKA).

cGMP

Cyclic guanosine monophosphate; formed by guanylyl cyclase; causes smooth muscle relaxation.

IP3

Inositol triphosphate; released from PIP2 breakdown by phospholipase C; triggers Ca2+ release from the ER.

DAG

Diacylglycerol; membrane-bound second messenger that activates protein kinase C (PKC).

Arachidonic Acid

Membrane fatty acid converted into eicosanoids via cyclooxygenase, lipoxygenase, or epoxygenase pathways.

Ca2+

Calcium ion; binds to calmodulin to activate enzymes and signaling cascades.

G-Protein Acting via Adenylyl Cyclase

Activates or inhibits adenylyl cyclase to convert ATP to cAMP, which activates PKA.

G-Protein Acting via Phosphodiesterase

Breaks down/cleaves cyclic nucleotides like cGMP into GMP and makes Guanine

G-Protein Acting via Phospholipase

αq subunit activates phospholipase C to hydrolyze PIP2 into DAG (stays at membrane level) and IP3.

PIP2 Breakdown

(PIP2) is split into DAG and IP3 by phospholipase C and opens channel for calcium release from Smooth ER

Calmodulin (CaM)

Ca2+-binding protein that activates target enzymes after binding FOUR calcium ions.

Three Major Pathways Convert AA to Eicosanoids

1) Cyclooxygenase → prostaglandins, thromboxanes, prostacyclins; 2) 5-Lipoxygenase → leukotrienes; 3) Epoxygenase → HETE & EET compounds.

Direct Pathway to AA Release

Activated G protein directly stimulates phospholipase A2 (PLA2) to release AA.

Indirect Pathway to AA Release

Involves multi-step activation of PLA2 for AA release.

Prostaglandin Synthesis and NSAID Inhibition

Cyclooxygenase converts AA into prostaglandins; NSAIDs inhibit COX to reduce inflammation.
 
Protogladnin synthesis related to mechanisms of cardio, cancer, and inflammatory dieases

Cortisol

Natural glucocorticoid hormone with anti-inflammatory properties.

Hydrocortisone

Active form of cortisol; acts immediately.

Cortisone

Precursor converted into hydrocortisone in tissues.

(small G-Protein)

Inactive Ras bound to GDP; becomes active when GDP is exchanged for GTP. can lead to activatation of Raf-1 to MEK to MAPK leads to transcription factor

Receptor Guanylyl Cyclase

Converts GTP to cGMP when activated by ligands like ANP; causes vasodilation and Na+ excretion.

Receptor serine/threonine kinases

Phosphorlyases

Atrial Natriuretic Peptide (ANP)

Ligand that binds receptor guanylyl cyclase in smooth muscle, causing blood vessel dilation and natriuresis 

How does Ca+ effect Receptor Guanylyl Cyclase

bind to RGC → cGMP → increase Ca+ intracell → relax smooth muscle  →  blood vessels dilate → increase blood vessel

Natriuresis 

enchances Na+ excretion into urine (more Na+ less H2O in blood)

Nitric Oxide (NO) and Its Role

Gas that diffuses into smooth muscle, activates SOLUBLE guanylyl cyclase, increases cGMP, and relaxes vessels. Irons binds here

Soluble Guanylyl Cyclase

Cytosolic enzyme activated by NO to convert GTP to cGMP.

Particulate Guanylyl Cyclase

Membrane-bound enzyme activated by ANP; converts GTP to cGMP.

Nitric Oxide Synthase (NOS)

Enzyme in endothelial cells that synthesizes NO from arginine into citrulinne plus NO (slower activity more longer term effect 

Nitroglycerin

Releases NO to relax smooth muscle and relieve angina pectoris (chest pain that accompainies inadequate blood flow to the heart muscle) by reducing work of the heart 

PDE5

Phosphodiesterase type 5; breaks down cGMP; target of Viagra. Inhibits cGMP degradation, enhancing vasodilation. It can affect our eyes.

Viagra (Sildenafil)

Inhibits PDE5, prolonging cGMP for smooth muscle relaxation.

Receptor Tyrosine Kinases (RTKs)

Receptors with intrinsic kinase activity; phosphorylate tyrosine residues; respond to EGF, PDGF, VEGF, insulin, etc. (Lot of growth Factors)

Nuclear Receptors (Detailed)

Steriod and thyroid horomones enter the cell and bind to nuclear receptor superfamily in the cytoplasm/nucleus and binds to DNA

bind to speciifc DNA sequience called hormone response elements in the regulator region

Ligand-Activated Transcription Factor

Receptor that, when bound by ligand, directly binds DNA and initiates gene transcription.