Chapter 5: Control of cells by chemical messengers Flashcards
Intracellular Chemical messengers
- include hormones and neurotransmitters
- require chemical messenger binds to specific receptors on target cells and requires signal transduction proceeds, sequence of intracellular events in response to chemical messengers
Receptor composition
- proteins and glycoproteins
receptor locations
- plasma membrane (interact with water-soluble/transmembrane chem messengers)
- nucleus (interact with lipid-soluble chem messengers)
receptor specificty
- only specific receptors will bind particular chemical messengers
- mostly bind with only 1 chemical messenger
- different cell types possess receptors for particular messengers (ligands)
- different cell types may have receptors for the same chemical messenger
- a single cell type may contain more than one receptor type for a single messenger
receptor affinity
- can have different affinity for different chemical messengers
receptor saturation
- may be saturated via chemical messengers
receptor competition
- antagonists and agonists
antagonist
- binds to a receptor
- does NOT trigger cell’s response
- blocks the receptor from binding to its proper chemical messenger
- example: beta blocker
agonist
- binds to receptor
- triggers the cell’s response
- mimics the messengers response
Down regulation
- decrease in total number of target cells receptors for a given messenger
- response to chronic high extracellular messenger concentration
Up regulation
- increase in total number of target-cell receptors for a given messenger
- response to chronically low extracellular messenger concentration
- supersensitivity
mechanisms in which up/down regulation occurr
- receptor synthesis or degredation
- alterations in gene expression –> code for receptors
signal transduction pathways
- sequence of events leading to ultimate cellular response
- initiated by receptor activation
receptor activation
- change in the conformation of the receptor induced by binding of chemical messenger
types of cellular responses
- changes in the permeability, transport properties, or electrical state of the cell’s plasma membrane
- changes in the cell’s metabolism
- changes in the cell’s secretory activity
- changes in the cell’s rate of proliferation or differentiation
- changes in contractile activity
signal transduction pathways initiated via lipid-soluble messengers
- steroid hormones, thryoid hormones, 1,25-dihydroxy vitamin D
- involve intracellular receptors most located in nucleus (in cytoplasm too, but rare)
- activation alters rates of gene transcription
signal transduction pathways initiated via water-soluble messengers
- most hormones, neurotransmitters, and paracrine/autocrine compounds
- receptors are located in the plasma membrane
- 4 types of receptors:
1) receptors are ligand-gated channels
2) receptors are ions
3) receptors are bound to and activate JAK kinases
4) G-protein-coupled receptors
first-messenger
the intracellular chemical messenger that binds to the plasma membrane receptor (hormone or neurotransmitter)
second-messenger
- a substance that enters or is generated in the cytoplasm in response to receptor activation by the first messenger; serves as a chemical relay to the interior of the cell
receptors that are ligand-gated ion channels
- receptor activation by a first-messenger –> conformational change in the receptor –> opens the channel through the plasma membrane
- increased diffusion of one or more types of ions across the plasma membrane (change in the mem potential)
- increased cytosolic calcium concentration is important in many signal transduction pathways
Receptors that function as enzymes
- majority are receptor tyrosine kinases!
Mechanism of action of receptors function as enzymes
- receptor activation
- conformational change
- activation of enzymatic portion of the receptor
- autophosphorylation
- formation of phosphotyrosines
- phosphotyrosines serve as docking sites for cyotoplasmic proteins (docking proteins)
- bound docking proteins bind and activate other proteins, which activates one or more signaling patways
- cellular response (usually an effect on cell proliferation or differentiation)
exception with receptors as enzymes
- receptor acts as a guanylyl cyclase
- catalyzes formation of cyclic GMP (cGMP) in the cytoplasm
- cGMP acts as a second messenger, activates cGMP-dependent protein kinases that phosphorylates proteins involved in the transduction pathway (cells response)
- found in large amounts in the retina; involved in processing visual inputs
Receptors that interact with cytoplasm JAK kinases
- receptor is associated with cytoplasmic JAK kinase (tyrosine kinase) –> function as a unit
mechanism of action of receptor with cytoplasm JAK kinase
- binding of first messenger
- conformational change in receptor
- activates JAK kinase
- JAK kinase phosphorylates a protein or proteins (many act as transcription factors)
- synthesis of new proteins that mediate cell’s response
G-protein-coupled receptors
- largest category
- g-protein complex located on the cytoplasmic surface of the plasma membrane is bound to receptor
mechanism of action of g-protein-coupled receptors
- binding of a first messenger to receptor activates it
- change in receptor conformation
- increased affinity of alpha subunit of g protein for GTP
- GTP binds to alpha subunit
- dissociation of the alpha subunit from g-protein complex
- alpha subunit links to another plasma membrane protein (plasma membrane effector protein)
Gs vs Gi proteins
- Gs: activate adentltl cyclase –> cAMP production
- Gi : inhibit adentltl cyclase activity –> decrease cAMP production
phospholipase c, diacylglycerol, and inositol triphosphase mechanism of action
- receptor activation by 1st messenger
- activation of Gq
- activation of phospholipase C
- catalyses breakdown of PIP2 into diacyglyerol and inositol triphoshate which become second messengers in cell
- diacyglycerol activates protein kinase C enzymes that phosphorylate other proteins –> cells response
- IP3 binds to receptors (ligan gated Ca++ channels) on endoplasmic reticulum which open channels and calcium diffuses out of ER into the cytoplasm –> biochem events –> cells respons
control of ion channels by G proteins
- direct gprotein gating
- indirect gprotein gating
calcium as second messenger
- plasma membrane Ca++ channels can be ligand-gated or voltage-gated
- calcium acts as second messenger by binding to various cytosolic proteins and altering their conformation
cyclooxygenase inhibitors
- asprin and nonsteroidal anti-inflamm drugs
- inhibit production prostoglandins and thromboxates
- steroids inhibit phospholipase A2
Eicosanoids
- stimulate inflammation and in immune response
- drugs act to inhibit production of eicosanoids by inhibiting cyclooxygenase or phospholipase A2
- generated by poly-unsaturated acid which is part of membrane phospholipids
- first messenger binds to receptor activating phospholipase A2
- A2 splits off arachondonic acid from membrane phospholipids
- arachodonic acid is metabolized in 2 ways
arachodonic acid metabolized
1) acted on by enzyme lipo-oxygenase –> lucotryannes
2) acted on by enzyme cyclo-oxygenase –> cyclic endoproxide–> either prostaglandin or thromboxates
receptor activation ceases in signal transduction pathways
- decrease in amount of first messengers
- receptor inactivation
- -> chemically alteres (phosphorylated)…lower its affinity for the first messenger or prevent G-protein binding
- internalized by endocytosis
