bi203-- cell communication: chemical messengers and receptors

why is cell communication important

• coordination of their diverse activities to maintain homeostasis

• to control growth and development of the animal as a whole

mechanisms of intercellular communication

Direct: through gap junctions— cells exchange chemicals through connections between cytoplasm

indirect: through chemical messengers— messenger must bind to a matching receptor and stimulate a response

direct communication: gap junctions

• formed by plasma membrane proteins (connexins) that form structures (connexons) that form channels for ions and small molecules

• movement of small molecules through gap junctions metabolically couple the cells and causes of organs to act as a unit

indirect cell communication: chemical messengers

• most common through intercellular chemical messengers

• chemical messengers (ligands) synthesised by specialised cells to serve designated purpose

• once in extracellular fluid these signalling agents act on other cells

• ligands must bind with receptors on the target cell that are specific to that ligand

• receptors are typically integral proteins in the plasma membrane

• given cell may have a few million receptors

• different cell types have distinct combos of receptors, allowing them to react individually to various regulatory extracellular chemical messengers

chemical messengers: functional classification

• paracrine: cell secretes chemical which can bind to receptor on neighbouring cell triggering a response e.g. histamine secreted for inflammation

• autocrine: cell secretes chemical which can bind on its own membrane and stimulates a response— critical in cancer activation and providing self sustaining growth signals to tumours

• neurotransmitter: released from neurons through axons and act on neighbouring cells e.g. serotonin (not only a neurotransmitter “same key, different lock”)

• hormone: long range chemical messengers that are specifically secreted into circulation by endocrine glands, carried in circulation to target cells e.g. insulin is secreted by pancreas

signal transduction (ST)

• chemical messengers usually dont trigger change sin target cells directly— trigger biochemical chain of events in cell called signal transduction

1. reception: cell receives signal

2. transduction: pathway of several steps with each molecule in the pathway bringing about a change in the next step

3. response: pathway triggers cellular response

chemical messengers must bind to receptors

cellular receptors for chemical messengers

• membrane bound/ intracellular

• specific for chemical messengers

• multiple receptors on each cell

• responsiveness regulated by up or down regulation of cellular receptor

e.g. cell A has matching receptor for chemical messenger so only one that responds

outcomes of receptor binding by chemical messengers

• extracellular chemical messengers not usually trigger changes in target cells directly

• some cant even enter target cells

• most messengers issue orders by binding with specific receptors— triggers signal transduction

• two types of chemical messengers

1. lipid soluble (lipophilic): bind to intracellular receptors (e.g. steroid hormones)

2. lipophobic (poorly soluble in lipid): bind to cell surface receptors inducing conformational change which in turn activate signal transduction pathways

lipid soluble messengers—e.g. oestrogen

cross lipid membrane and bind to intracellular receptors

mechanism

1. free lipid soluble messenger diffuses from blood through interstitial fluid and through lipid bilayer of the plasma membrane

2. if cell is target cell and has appropriate receptors the messenger will bind to form a receptor messenger complex- -act as transcription factors

3. DNA transcribed producing mRNA which is translated into protein (enzymes)

4. new proteins alter cells activity and cause responses typical of that messenger

lipophobic messengers

• not lipid soluble therefore cannot diffuse through membrane lipid bilayer

• instead bind to receptors on the surface of the plasma membrane

• receptors are integral proteins of the plasma membrane

• binding of the messenger to the receptor acts as first messenger

• first messenger causes conformational changes in the receptor that activate signal transduction pathways, that ultimately bring about a cellular response

how do lipophobic chemical messengers (first messenger) bring cellular effects?

• cant cross plasma membrane

• bind to receptors in plasma membrane to exert their effects

• brings about the desired intracellular response by only three general mechanisms:

1. by opening or closing specific channels in the membrane to regulate the movement of particular ions into or out of the cell

2. by activating an enzyme that phosphorylates a cell protein

3. by transferring the signal to an intracellular chemical messenger (second messenger) which in turn triggers a series of biochemical events within the cell

classification of plasma membrane receptors

1. ion channel receptors: plasma membrane receptors that open/ close ion channels when bound to specific ligand

2. receptor than function as enzymes: plasma membrane receptors/ enzymes that are activated once ligand is bound

3. G protein coupled receptors: plasma membrane receptors that activate GTP binding proteins

receptors functioning as ion channels

• some first messengers bind to receptors that open or close gated receptor channels that regulate movement of particular ions across the membrane

• receptor are specific for a single ion

• activation of the receptor by a first messenger causes conformational change and either opening or closing of the ion channel

• ions move from where they are more concentrated to where they are less concentrated

• cations will move towards negative areas and anions will move towards positively charged area

e.g. acetylcholine (ligand) released by neurons binds to the acetylcholine receptor on target cells resulting in entry of Na+ down concentration gradient into cell

-what happens when ions flow in and out of cell

1. changes in plasma membrane potential (Na+,K+)

2. ions may act as second messengers (e.g. CA2+)

cellular effects of ion movement— changes in plasma membrane potential

• all cells maintain a voltage across their plasma membranes

• only excitable cells can generate action potentials, the rapid transient changes in membrane potential that spread along the surface of these unique cells

• action potentials transmit information within neurons, trigger contractions within muscle cells, and lead to exocytosis in secretory cells

cellular effects of ion movement— effect of increasing intracellular calcium(CA2+)

• transient flow of Ca2+ into the cell through opened Ca2+ channels triggers:

• an alteration in shape and function of specific intracellular proteins

• activates multiple cellular functions such as muscle contractions, release of secretory products from gland cells and cell division

receptors functioning as enzymes

• receptors functioning as enzymes have dual role— they bind ligand and have an enzymatic function

• contain an enzymatic domain on their intracellular side

• majority of enzymatic receptors are protein kinases, which phosphorylate proteins in the target cell

• phosphorylated proteins then recruit and activate other intracellular proteins which infiltrate a protein kinase cascade

protein phosphorylation

• transfer of a phospahte group from ATP to a protein (on serine, tyrosine or threonine residues (phosphomotifs))

• catalysed by protein kinases

• phosphorylation regulates protein function and cell signalling by causing conformational changes in phosphorylated protien (activating or inactivating it)

• effects of protein kinases are reversed by protein phosphatases

regulation of protein phosphorylation

1. removal of activating ligand

2. kinases or substrate proteolysis

3. phosphatase-dependent dephosphorylation

protein phosphorylation example: tyrosine kinase receptors

• hormone insulin exerts effects through tyrosine kinases receptors, amino acid tail has series of tyrosines— in absence of ligands the tyrosine kinase receptors exist as a single polypeptide

• part of receptor on cytoplasmic side serves as an enzyme which catalyses the transfer of phosphate groups from ATP to the amino acid tyrosine

process of activation

• two signal molecule bind to two nearby tyrosine kinase receptor, causing them to aggregate forming a dimer

• formation of dimer activates tyrosine kinase portion of each polypeptide

• activated tyrosine kinases phosphorylate the tyrosine residues on the protein

activated receptor protein is now recognised by specific relay proteins

bind to phosphorylated tyrosines and the receptor phosphorylates the relay proteins, activating them

activated relay proteins can then trigger cellular response

one activated tyrosine- kinase dimer can activate over ten different relay proteins, each which triggers a diff response

receptors that interact with G proteins (G protein coupled receptors)

• largest category of plasma membrane receptors

• extracellular ligand binding region and an intracellular region that binds a ‘G protein’

• ‘G proteins’ bind to guanine nucleotides: GTP active, GDP inactive (think ATP and ADP but G instead of A)

• binding of ligand to receptor changes confirmation of receptor which frees the G protein and allows it to interact with effector proteins

• effector proteins can be ion channels or enzymes

• activated effector protein amplifies the signal from the ligan via second messengers

1. -2) extra cellular (first messenger) binds to receptor causing confirmational change activating the G protein (GDP→ GTP)

3. active G protein travels along plasma membrane and activate effector protein

4. effector protein produces ‘second messenger’

5. second messenger activates a protein kinase

6. -7) phosphorylation cascade brings about desired cellular response