Lecture 11: cell to cell communication Flashcards
Direct signalling uses
Gap junctions, which connect cells directly touching each other
- the signal therefore passes directly from one cell to another without traversing extracellular space (stays in the cytoplasm)
- ie. contraction of cardiac cells
Gap Junctions
- specialized protein complexes create an aqueous pore between adjacent cells
- can be opened or closed for regulation
- allows rapid communication over short distances
Indirect signals must be:
- synthesized & stored, released, transported
- received and transduced by the receptor
- transduced and amplified by signal transduction pathway, so target cell can generate a response
Chemical Messenger-problems
- must be transport in aqueous solution, if messenger is not water soluble it will have trouble over long distances
- message has to penetrate cells, so if it is not lipid soluble it cannot send its signal
Receptor locations
- embedded in the membrane with binding site outside the cell
- inside the cell
Ligand binding
-ligand or chem messenger binds to the receptor to induce change in its conformation and activates the signal transduction pathways that cause response in the cell
Receptor Specificity
-ligand binding site has a specific shape, so only some molecule fit its structure
agonists and atagonists
- chemicals that bind to and activate receptors are agonists, the mimic natural ligands
- antagonists bind to the receptor but block the action of the natural ligand
Adenosine
-a purine nucleoside functions for: energy transfer (atp, adp), signal transduction (cAMP), promotes healing, and as a neurotransmitter inhibits activity in the CNS*** causing sleepiness and preventing arousal after prolonged mental activity
Caffeine, adenosine antagonist
- binds to and blocks adenosine receptors in the CNS
- is both water and lipid soluble, can cross blood-brain barrier
- cells respond by increasing amount of adenosine released, which is why coffee drinkers must have more to overcome increasing adenosine levels
Receptor Saturation
- single cell expresses many molecules of a given receptor
- the more receptors that are bound to ligand, the larger the magnitude of the response
- saturation=all receptors are bound to ligand
- increasing # of receptors means increased response
up and down regulation
of receptors on a target cell can change over time
Receptor sensitivty
-affinity of a receptor for a ligand
Dissociation constant Kd=
the ligand concentration at which HALF the receptors are bound to ligand
Affinity constant
Ka=1/Kd; as Ka increases, response increases
Inactivation of ligand signaling
- remove from ECF
2. terminate receptor activation
Removing ligand from ECF
- enzymes in liver and kidney break down hormoes, removing them from the blood (slow)
- ligand will be destoryed at the cellular levels (fast)
Terminating receptor activation
-as concentration of a hormone in the ECF decreases, bound molecules of that hormone will dissociate from their receptors
inactivation of ligand signaling
-receptor down regulation, receptor sequestration, receptor inactivation, inhibitory proteins, signal protein inactivation
Signal transduction pathways amplify signals
-convert conformational change of an activated receptor into an intracell response
-signald transduction pathways have multiple steps
-greater the number of steps, the greater the amp
“each activated receptor activated many substance A, which activates many B, etc)
4 types of receptors
- intracellular
- ligand-gated ion channel
- receptor-enzyme
- G-protein-coupled receptor
Intracellular receptor location
in cytoplasm (move to nucleus once bind to ligand) or in the nucleus, bound to DNA
- ex: ER-a estrogen receptor, found in hypothalamus, ovary, uterus, and mammary glands
- over-expressed in 70% of patients with breast cancer
intracellular receptors regulate transcription
- of traget genes by binding to specific DNA sequences and increasing or decreasing mRNA production
- have 3 domains: ligand binding, DNA binding, and transactivation
- many endocrine hormones bind to them (estrogen, testosterone, etc)
Ligand-gated ion channels
- when activated by binding ligand, the receptor changes shape, opening or closing the ion channel, allowing ions to pass and change MP
- ie. Nicotinic ACh receptor
Receptor enzyme
- when activated the catalytic domain starts a phosphorylation cascade
- 3 subtypes: guanylate cyclase (few), tyrosine kinase (majority in animals), serine/threonine kinase (many)
Receptor guanylate cyclase
- when activated catalyzes conversion of GTP to cGMP
- cGMP acts as secondary messenger in signal transduction pathway
- ie. atrial natriuretic peptides
receptor serine threonine kinase
- serine and threonine residues phosphorylated by protein, initiating a long phosphorylation cascade
- ie. transforming growth factor beta
receptor tyrosine kinases
- phosphorylation of the receptor creates high affinity docking sites for the binding of specific intracellular signaling proteins
- intracellular proteins bind between themselves, becoming phosphorylated and activated
- often bind growth factors or insulin, and are involved in cell growth and proliferation
- ie. Ras, GAPs, GNRP
tryosine kinases and growth factor
- activated Ras signals start amplification cascade/phosphorylation cascade
- MAP-kinase phosphorylates a variety of target proteins (MAPK=mitogen activated protein kinase
- mutation of this receptor and transduction pathway can cause cancer, due to its effect on cell growth and metabolism
Vascular endothelial growth factor (VEGF) receptors
- tryosin kinase receptors located in cell membrane of endothelial cells lining blood vessels
- when activated by VEGF, induces cell proliferation and growth of new blood vessels (angiogenesis)
- VEGF is produced by cells which are not receiving enough oxygen
G-protein-coupled receptors (GPCR)
- transmembrane receptors which interact with heterotrimeric G proteins
- ligand bindings induces conformational change, causing the alpha subunit to release GDP and bind GTP
- alpha and By subunit (aka G protein) become active and dissociate, allowing them to move through membrane to interact with ion channels or amp enzymes and initiate or mute a response
- alpha subunit remains active until it hydrolyzes GTP, at which point it becomes inactive and reassembles with By
speed of alpha subunit hydrolysis of GTP can be regulated
- alpha subunits are slow GTPase
- RGS are proteins that control speed of a subunits’ hydrolysis of GTP, activating RGS speeds up hydrolysis
GPCR signal transduction pathways
- a and By can stimulate ion channels to open or close, changing MP and ion concentration (ie. acetylcholine on cardiac cells)
- a and By subunits activate or inhibit amplifer enzymes such as adenylate cyclase, guanylate cyclase, phosphodiesterase, phospholipase
ie. for cAMP signal trans. path. Gs activates adenylate cyclase and Gs inhibits it
- can also regulate levels of cAMP to reg. levels of active PKA
GPCR example: taste receptors
- modified epithelial cells that release neurotransmitter onto afferent neurons
- each receptor expresses more than one type of taste receptor protein
G-proteins regulate activity of phosphodiesterase
dark: -Na+ gate channel maintained open by cGMP that bind on it
- Na+ enters the cell, contributes to resting value of Em
G-proteins regulate Phospholipase C
- phos. C breaks down PIP2 into DAG and IP3
- DAG activates PKC, which initiates a phosphorylation cascae
- IP3 releases Ca2+ from endoplasmic reticulum as a secondary messenger
GPCR-Ca2+ activates calmodulin
- some g-proteins open or close Ca2+ channels directly or indirectly
- Ca2+ binds to calmodulin & binding 4Ca2+ activates calmodulin
- activated calmodulin regulates over 100 cellular proteins
ex: increased Ca2+activates calmodulin->activates CaM kinase II->phosphorylase tyrosine hydrolase->increase synth of catecholamines
GPCR example: angiotensin receptor
- hormone produced by liver that increases blood pressure
- found in smooth muscles lining blood vessles and activates the subunit of G-proteins, activation phospholipase C
- IP3 releases Ca2+ from the ER, stimulating muscle contraction=vasoconstriction
Signal transduction pathways can interact with each other:
- when bound to Ca2+, calmodulin interacts with adenylate cyclase, which produces cAMP
- Ca2+-calmodulin can also interact with cAMP phosphodiesterase, which breaks down cAMP
- cAMP activates PKAA, which can phosphorylate Ca2+ channels and pumps, increasing or decreasing their activity
