Cell Signaling

Cell signaling

• Cell signaling affects ion transport, exocytosis, endocytosis, lamellipodia and filopodia

 

• Cell communicate with 1 another using extracellular messenger molecules (ligands) that associate with transmembrane proteins (receptors)

Endocrine

• Produce far away from target tissue

• Reaches target by circulatory system

• Ex: hormones, distributed widely by bloodstream

Paracrine

• Diffusible and act "locally" or over short distances

• Distribution is limited because its inherently instable

Autocrine

• Acts on the same cell that produces them

• Cell stimulate/inhibit itself

Contact Dependent

• GPI or transmembrane domain on signaling cell physically contacts target

Amino Acids and Derivative Ligands

• Ex: Acetylcholine and epinephrine

• Many of the molecules act as neurotransmitters and hormones like epinephrine (derived from tyrosine)

Steroid Ligands

• Ex: estrogen and cortisol

• From cholesterol derivatives

  • Regulate sexual differentiation

  • Pregnancy

  • Carbohydrate metabolism

  • Ion excretion

Eicosanoid Ligands

• Ex: Prostaglandin A2 and Leukotriene B4

• Fatty acids that regulate pain, inflammation, blood pressure and blood clotting

• NSAIDS (advil) block their syntheiss

Polypeptides and proteins

• Ex: oxytocin and insulin

• A wide variety of secreted proteins act as ligands regulating processes

  • Cell division

  • Differentiation

  • Cell death/survival

  • metabolism

Receptor/Ligand Binding and Specificity

• Receptor/ligand binding is similar to enzyme/substrate

• Receptor has a Binding site (binding pocket) that fit the ligand very closely

• Ligands bind to receptor in a high specific way by non-covalent interactions

• An occupied receptor I bound to ligand

Dissociation Constant Kd

• Measure of the affinity of a ligand to its receptor

Binding Specificity

• Ability of a receptor to distinguish between closely related molecules. Binding depends on the sum of multiple weak noncovalent interactions

Binding Affinity

• Strenght of binding is measured by the dissociation constant Kd

• Kd is the concentration of ligands to bind to 50% of receptors

• Receptors with high affinity of the ligand has a low Kd

  • Low concentration to occupy 50% of receptors

Agonists

• Drug that activate the receptor they are bound to

• Stimulate response and mimic natural function

• Ex: Isoproternol is used to treat asthma, its an agonist for epinephrine, creates a GPCR response on bronchial smooth muscles. Binds 10 times more strongly than epinephrine and activates bronchial relaxation of smooth muscles

Antagonists

• Drugs that bind receptors without activating. Prevents the naturally occurring messenger from activating

• Ex: Alprenolol can control anxiety attacks and cardiac arrhythmias

  • Its an antagonist that blocks the effect of epinephrine responses on cardiac muscle cells that increase heart rate contraction. Alpre

General Principles of Cell Signaling

1. ECF ligands or First messengers bind to a receptor

2. Receptors triggers a signal cascade

3. Ligand binding induces a conformational change in transmembrane receptor protein which ats to relay the signal across the membrane

4. The active cytoplasmic domain of receptor can act as or activate effector molecules

5. Effectors generate small molecules or ions that relay signals from one location to another in the cell referred as "second messengers"

6. Proteins at the "top" of the intracellular signaling pathway is activated

7. This causes a series of protein modifications to occur in a  specific sequence

   1. Each protein in the cascade acts on the subsequent protein to to alter its conformation to activate or inhibit the "downstream" protein

   2. Phosphorylation of a protein is most common

8. Target Proteins are reached which then activate a specific cellular process

General outcomes of signaling pathways

 

Receptor/ligand binding can have different outcomes depending on expression of different proteins in different cells

• Intracellular  signaling involves second messengers that can bind to other proteins an modify their activity

 

1. Initiates 1 or more intracellular pathway which results in change in

   1. Cellular function

   2. Metabolism

   3. Gene expression

   4. Shape/movement

Signals can combine in different ways to generate different outcomes

• Typical cell is exposed to hundreds of different signals

• Combination of signal generate crosstalk and different cellular responses

Second Messengers

• A small molecule that increases or decrease in concentration in  in response to first messenger

• Diffuse rapidly through cytosol

• Can be used to amplify a signal

 bind to other proteins and modify their activity

Kinases

• Phosphorylate protein

• Add phosphate group on OH

Phosphatases

• Dephosphorylate protein

• Remove phosphate group

Types of Kinases

• Tyr kinase

• Ser/Thr Kinase

• Dual Specificity

  • Tyr/Ser/Thr

Integration

Cells can be exposed to many signals at any moment and must integrate the signals to produce appropriate responses

Divergence

• Signal from 1 ligand/receptor can activate effectors in different pathways

• 1 receptor activates many pathways

Convergence

• Signals from many unrelated ligands/receptors can converge to activate common effectors

• Different receptors activate the same pathway

Crosstalk

• Signals from different pathways can effect components of multiple pathways

• Passes information back and forth

• Different receptors activate different pathways; 1 pathway affects the other

Cell surface receptors

• Most signaling molecules are hydrophilic and unable to cross the plasma membrane

• Bind to cell-surface receptors

Intracellular Receptors

• Small hydrophobic signaling molecules that diffused across membrane

• Bind to receptor protein in cytoplasm or nucleus

  

3 calsses of cell-surface receptors

• Ion-channel coupled receptors

  • The binding of the ligand opens the channel

• G-Protein Coupled Receptors

  • Inactive receptor, inactive G protein and inactive enzyme

  • A ligand binds to the receptor, activates the receptor and G protein

  • Activated G protein subunits activate the enzyme

• Enzyme-Coupled Receptors

  • A signal molecule forces a dimer, which binds to receptors to form a dimer and activate the catalytic domain

  • A signal molecule binds to a receptor to form a dimer and activates an associated enzyme