Cell Signaling and Receptors

chemical messengers

-Chemical messengers (hormones, neurotransmitters, etc.) bind to proteins called receptors

*for communication, to active homeostasis loops, etc.

-Most chemical messengers are water-soluble and bind to receptors located at the plasma membrane

*travel easily in blood and ECF; bc can’t cross the membrane

-Some messengers, like steroids, are lipid-soluble and bind to an intracellular receptor

*can go through the membrane

receptor specificity

-Cells only respond if they have the correct receptor (“lock and key”)

-Chemical messengers can activate multiple receptor types, with each having a different response

Receptor Terminology

-ligand

-endogenous ligand

-agonist

-antagonist

-Ligand: a molecule that binds to a receptor

• natural or synthetic (ex: drugs); activate or block

-Endogenous ligand: hormone or neurotransmitter produced by the body (naturally produced)

-Agonist: a molecule that binds to a receptor and activates it

• usually natural, most hormones and NT; ex: epinephrine

-Antagonist: a molecule that binds to a receptor and blocks it, preventing activation by an agonist and other binding

• usually a drug; ex: beta-blocker prevents epinephrine from binding

nuclear receptor

-Inactive receptor can be found in cytosol or nucleus

• for lipid soluble messengers, usually steroid hormones (ex: cortisol)

-Activated receptor translocates to nucleus and binds DNA

• switch genes on or off/changes transcription of RNA

*picture: “N-terminal” protein; DNA-binding site; ligand-binding site

pathways initiated by lipid-soluble messengers

-usually slower effects (bc takes time to make proteins)

*lipid often bound to a protein to travel

Transmembrane receptors

-Protein structure crosses the membrane one or more times

-Extracellular domain binds to signaling molecule

-Intracellular domain activates signaling pathway inside cell

-Alternatively, some transmembrane receptors form channels that allow ion flux (ex: ligand-gated ion channels)

*picture: G-protein (know bc 7 transmembrane structures)

Ligand-Gated Ion channels

-Agonist (ligand) binding causes channel to open (or close)

-Main effect is change in membrane potential

• (+) ions in: depolarizes cell (can generate AP)

• (-) ions in: hyperpolarizes cell

• (+) ions out: hyperpolarizes cell

-ex: nicotinic acetylcholine receptor (Ach=ligand); just “ion-channel”=voltage gated

Enzyme-linked receptors

-Example: receptor tyrosine kinase

• extracellular receptor; tyrosine intracellular; kinase adds phosphate

-Receptor has enzyme activity that phosphorylates target proteins in cell

• phosphorylates tyrosine (on/off switch)

-other ex: Insulin receptor

Receptors that Interact with Cytoplasmic Kinases

-JAK/STAT pathways (*full name)

-Receptor activates Janus kinase (JAK) which goes on to phosphorylate proteins in the cytoplasm

-Often transcription factors that go to nucleus

• “stat”: transcription factor protein that goes to the nucleus, similar to steroids

-usually slower

-ex: growth hormone

G Protein-Coupled Receptors (GPCRs)

-G protein is located on cytoplasmic surface of plasma membrane

-Three subunits; Activated alpha subunit binds GTP and dissociates from beta and gamma

-Goes on to activate enzymes and ion channels

*common for NT and hormones (ex: epi and norepi, dopamine); G protein doesn’t directly cause a response

G Protein Classifications

-Gs: stimulates adenylyl cyclase, increases cAMP

-Gi: inhibits adenylyl cyclase, decreases cAMP

-Gq: activates PLC, leading to increases in IP3 , DAG and Ca2+ (second messengers)

Gs-coupled receptors

-Adenylyl (adenylate) cyclase: enzyme that makes cyclic adenosine monophosphate (cAMP) from ATP (ATP → cAMP)

-cAMP is a second messenger that activates cAMP-dependent protein kinase (PKA)

formation and breakdown of cAMP

-adenyl cyclase: catalyzes reaction, increase cAMP

-cAMP phosphdiesteraste: terminates the response, decreases cAMP

signal ampplification

-purpose of 2nd messengers

-low [ ] of 1st messenger (stays outside, water soluble) leads to lots of the final product

-ex: NT and synapse; hormones in blood

actions of cAMP-depdenent kinases

-know an do a lot of things depending on the cell

Gq-coupled receptors

-Activated Gq activates an enzyme called phospholipase C (PLC)

-PLC catalyzes the breakdown of a plasma membrane phospholipid known as phosphatidylinositol bisphosphate, abbreviated PIP2 , to diacylglycerol (DAG) and inositol trisphosphate (IP3 )

• IP3 causes Ca2+ release from the endoplasmic reticulum

• DAG activates protein kinase C (PKC)

*mainly for Ca2+ signaling in cells; Ca2+=2nd messenger; PIP2=ligand, IP3 in EPR

Ca2+ as a second messenger: calmodulin and calmodulin-dependent protein kinase

-increase Ca2+ from plasma membrane channels OR the EPR → increased cytosolic Ca2+

-Ca2+ binds to calmodulin and activates it → activating calmodulin-dependent protein kinase

Summary of important 2nd messengers

*cAMP and cGMP similar idea

Arachidonic Acid and Eicosanoids

-phospholipase A2: cuts off lipids tails

-Arachidonic acid: 20C chain from cut off tail

*then can do option a or b…

a) Cyclooxygenase pathway (aspirin blocks this)

• Prostaglandins: inflammation

• Thrombaxnes: blood clotting (platlete activity)

b) Leukotrienes: allergic and inflammatory reactions, asthma

How are signal transduction pathways turned off?

-Agonist diffuses away from receptor (*usually reversible binding and weak bond)

-Second messenger can be degraded by enzymes (*ex: phosphoaesteas)

-Calcium pumped back into endoplasmic reticulum (*at rest: low Ca2+ in cytosol bc of this)

-Longer term decreases in signaling

• Phosphorylation of receptor (*P turns it off)

• Internalization of receptor (*receptor removed from membrane)

• Downregulation: decreased synthesis of receptor protein (*if receptor overally activated)

Comparison of receptor types (summary)

LGIC, RTK, JAK and GPCR

-Located on cell membrane

-Transduce an extracellular signal into an intracellular signal

• Membrane potential

• Phosphorylation

• Generation of second messenger

-Can lead to gene transcription changes as a downstream effect (*steps between)

Nuclear receptors

-Located in cytosol, translocate to nucleus when ligand binds

-Main effect is (direct) regulation of gene transcription