Lecture 15: Cell signalling, signal transduction, receptors, GPCR, G proteins, disease implications

Cell signalling

Communication between cells to carry out specific tasks or functions

What cell signalling regulates

Cell growth and division

Types of intracellular signalling

1. Autocrine: Cells have receptors on its surface that responds to EM

2. Paracrine: Messenger molecules travel short distances in extracellular space

3. Endocrine: Messenger molecules reach their target cell through bloodstream

What must a cell require to respond to extracellular message? 

Receptors

Ligand

Molecule that binds to the receptor

2 major types of signal transduction 

1. Second messenger (activate or inactivate specific protein)

2. Recruitment of protein

Describe signal transduction

Consists of kinase and phosphatases that change conformation and activities of target protein

Protein phosphorylation

Adds phosphate group to Ser, Thr, Tyr to change protein behavior

Activation of GPCR rhodopsin in vision cycle

Rhodopsin contains Opsin and cofactor Retinal

Retinol is produced in retina by beta-carotene. Isomerization of 11-cis-retinal into all-trans-retina by light induced conformational change in Opsin which activates G protein

Visual transduction pathway 

1. Light

2. Rhodospin cis-retinal —> trans-retinal

3. Activation of cGMP phosphodiesterase

4. Perception of vision

GPCR structure

1. Largest receptor family

2. 7 a-helix

3. 3 subunits (Alpha, beta, gamma)

Signal transduction process by GPCR 

1. Binding of signalling molecule to a GPCR

2. Changes the shape and activates GPCR

3. GPCR binds to G protein

4. GTP replaces GDP (G protein is activated)

5. G protein dissociates from GPCR and binds to associated enzyme

6. Changes the shape and activates enzyme

7. Enzyme triggers cellular response

8. G protein hydrolyses GTP into GDP+Pi (inactive again)

Termination of repsonse

1. Desensitization: Blocking active receptors from turning on additional GP

2. GRK: activates GPCR via phosphorylation

3. Arrestins: Compete with GP to bind with GPCR

Role of regulators of GP signalling (RGS)

Accelerates termination response

GP and Cholera toxin

• Modifies Ga subunit

  • Unable to hydrolyze GTP into GDP

  • G protein is constantly activated

  • Continues to stimulate adenylyl cyclase to create cAMP

  • Amount of salt and water increases

Disorder related to GPCR 

Retinitis pigmentosa (degeneration of retina)

Gain vs loss of function mutation 

Gains: Leads to active GP

Loss: Regulate binding activity of GP leading to disease or disorder