Cell communication and signalling

• Define the terms cell communication, cell signalling, signal transduction • List the different forms of cell communication • Describe the mechanisms of G-protein coupled receptor (GPCR) signalling, and the role of G-proteins Explain what second messengers are, with examples such as cAMP • Define the terms cell communication, cell signalling, signal transduction-List the different forms of cell communication-Describe the mechanisms of G-protein coupled receptor (GPCR) signalling, and the role of G-proteins • Identify how Receptor Tyrosine kinase signalling functions, and the role of tyrosine phosphorylation • Be able to name other forms of cell signalling such as steroid hormone andnitric oxide (NO) signalling

Use short peptides- responses are Grow/divide Die Escape from immune cells

Use peptides, proteins, AA’s, nucleotides, steroids, retinoids, FA’s, gases (NO) Can attract other cells, tell them to move away, to die, grow, divide E.G hypoxia- cells release VEGF protein which causes blood vessel growth, leading to more oxygen supplied to organ. E.G Knee jerk reflex- nerve/spinal signalling E.G Neutrophil hunting bacteria

See lecture 45 table

Local • contact • cell cell signalling • Paracrine- cells in same vicinity • Autocrine • Synaptic Long distance -Endocrine-hormonal e.g insulin, adrenaline, thyroid - Neuronal- short and long distance- diffusion of NT across synaptic cleft to target cell, LD as nerve body can be long distance from cleft e.g breathing phrenic nerve (neuron) and diaphragm (muscle cells, NM junction)

Paracrine signaling: signaling in which the target cell is close to the signal releasing cell, and the signal chemical is broken down too quickly to be carried to other parts of the body. example of Paracrine Signalling: Insulin-like growth factor (IGF-1) signalling in Melanoma Clotting agents in thrombus formation Inflammatory mediators e.g. TNFa

A form of signaling in which a cell secretes a chemical messenger that signals the same cell. Examples of Autocrine Signaling: -Cancer cells -Interleukin-I (IL-1) in monocytes(immune) -IL-2 signalingin T-cells

food > increased blood glucose> release of insulin from pancreas (islets of langerhans)> insulin travels in blood to stimulate glucose uptake into blood, muscl, liver fat cells

Cells use specific receptors for cell signalling • response of cells depends on what receptors it expresses • same hormone can have different effects in different cells via the same receptor • each receptor is specific for its own ligand(“lock and key”)

Signal transduction pathways: basic model- membrane receptors allows hydrophyllic molecules to signal to the inside of the cell -the signal is transduced from the outside to the inside of a cell via intracellular signalling molecules -the signal can be fast or slow in terms of the cell responses Fast: adrenaline action on heart cells Slow: insulin action on liver

Signal transduction allows massive amplification of the signal- This means very low amounts of hormones, neurotransmitters can be effective in the body E.G- reception of light

Plasma membrane bound 1. G-protein coupled receptors 2. Enzyme-linked receptors 3. Ion channel receptors Intracellular receptors 4. Steroid hormones Local signalling-gases Nitric oxide

See lecture 45 Receptor > adaptor > effector Receptors e.g ion channels, GPCR, receptor tyrosine kinase Adaptors> adaptor proteins, scaffold proteins, molecular switches (messenger, amplifier and transducer proteins) Effectors- responses ( proliferation, migration, apoptosis, transcription, glucose uptake etc.) primary messenger binds to receptor outside cell - secondary messengers e.g cAMP brings about cellular responses

• examples of drugs that target GPCRs: • salbutamol (asthma) • b-blockers (hypertension) • serotonin-dopamine (L-DOPA) • angiotensin II blockers

G-protein Coupled Receptors (GPCRs)-GPCRs are proteins that span the membrane 7 times-1000s of GPCRs in the body, used by diverse ligands for rapid responses-examples: adrenaline, acetylcholine, dopamine, light, olfaction -largest drug target family in the body-1000s of receptors controlling heart rate, vision, smell

• G-proteins are made up of a and bg subunits • inactive G-proteins contain GDP bound to the a-subunit • activation of G-proteins by GPCR swaps GDP for GTP • active G-protein can then activate its effector and transmit the signal-signal turned off by the hydrolysis of GTP>GDP

G-proteins activate enzymes that generate “second messengers” in the cell -examples of second messengers are cAMP, IP3, DAG-second messengers are small molecules with key functions inside cells

• receptors form dimers that span the PM once • receptors are enzymes that phosphorylate tyrosine amino acids (the “on switch”) • RTKs used by insulin, growth factors, EPO etc. RTKs are enzymes that control cell growth, cell division “slower” cellular responses -many growth factors involved in tumour formation (EGF, VEGF)

Receptor Tyrosine Kinases activate effector enzymes directly • on/off switch for RTKs depends on phosphorylation of tyrosine • enzymes activated by RTK include MAPK, PI3K, Akt (ECB p557-559)

Some ion channels are receptors for extracellular ligands • channels for Na+, K+, Ca 2+ etc can be activated by ligand binding • ion channels are receptors for acetylcholine, glycine, GABA

GCPR- 1000’s of receptors • diverse ligands • 7 transmembrane domains • Regulation of effectors eg. AC,PLC, ion channels • Rapid responses • Physiological examples: Adrenaline: heart rate, Smell food: salivate RTK- Single transmembrane domain, activated by dimerisation • Direct regulation of effectors eg PI3K • Coupling to adaptor and scaffold proteins to transmit the signal e.g MAPK- Slower responses

NO- Diffuses rapidly to paracrine cells and triggers smooth muscle relaxtion. Target is guanylyl cyclase, generating cGMP and this causes vasodilation.