Cell Signalling & Diseases Flashcards
4 main types of receptors
- Ligand Gated Channel
- G protein Coupled Receptor
- Nuclear Hormone Receptor
- Receptor Tyrosine Kinase
Ligand Gated Ion Channel
- Mainly in the brain/nervous system and electrically excitable cells (conversion of binding to electrical signal)
- Binding of ligand/neurotransmitter brings conformational change to open gated channel
- binding can cause flow of ions which may cause excitatory effect, depolarisation or hyperpolarisation
- Allosteric binding controls opening and closing of ion channel, atimes has more than one allosteric site
- Ion movement causes changes in the potential of the cell
- GABAa receptors, 5-HT3
G protein coupled receptor
- Receptor spans the membrane 7 times
- Heterotrimeric receptor with 3 subunits, alpha, beta and gamma
- Binding of ligand causes binding to GTP and movement of beta and gamma subunits, conformational change
- alpha subunit dissociates and activate adenylate cyclase or Phospholipase C which activates cAMP or PIP2 (2nd messenger)
- Once ligand dissociates GTP is hydrolysed and the GDP binds causing inactivation of receptor and return of alpha sub unit
cAMP
1) Ligand (hormone and 1st messenger) binds to receptors allosteric site (inhibitory or stimulative)
2) Receptor activates G protein
3) G protein activates adenylate cyclase
4) Adenylate cyclase converts ATP to cAMP (2nd messenger)
5) cAMP activates protein kinases
6) Inactive protein kinases become active and bring a change in the cell
PIP2
1) Ligand (hormone and 1st messenger) binds to receptors allosteric site (inhibitory or stimulative)
2) Phospholipase C on cell membrane is activated
3) Phospholipase C hydrolyses PIP2 into secondary messenger IP3 and DAG
4) IP3 binds receptor on membrane of smooth endoplasmic reticulum and mitochondria to open Ca2+ channels
5) DAG helps activate Protein Kinase C
Hormones acting via cAMP include
-Adrenaline, Glucagon, ACTH, TSH, PTH, FSH, LH
Nuclear Hormone Receptor (Two types)
-Consists of 4 domains
N terminus (Variable)
DNA binding domain (Zinc finger+Phosphorylation site)
Hinge region - transport and nuclear localisation signal or HSP
-C Terminus: hormone binding then dimerization
-Excitatory and inhibitory receptor
-Hormone response complex moves to the nucleus and binds a specific regulatory sequence (HRE) in the DNA (promoter)
-This activates or represses transcription
Two types of steroid hormone receptors
-Type I (Steroid - Lipid soluble)- Binds to soluble cytoplasmic receptor protein in either cytoplasm or inside the nucleus, if required will be transported to nucleus, hormones must be lipid soluble. Sex hormones, cortisol receptors and mineral corticoid receptors
1) Lipid hormone binds nuclear receptor with NR/HSP complex
2) HSP dissociates to leave NR/Hormone complex, NR dimer then formed
3) NR Dimer moves into nucleus, co-activator and RNA pol bind
4) RNA pol on complex binds HRE translates mRNA strand of target gene
5) The target protein is activated and transcribed
-Type II (Peptide - Water soluble) - Binds directly to DNA N terminus . Vitamin A, D, Retinol and thyroid hormones
1) Peptide enters nucleus through pore and binds LBD/DBD complex bound to HRE causing co-repressor to dissociate
2) RNA pol and co activator bind LBD/DBD complex
3) RNA pol on complex binds HRE translates mRNA strand of target gene
4) The target protein is activated and transcribed
Receptor Tyrosine Kinase
- Transmembrane protein that can act as enzymes once bound to by ligand and work in pairs
- Cross linking of tyrosine kinase activates the tyrosine kinase through phosphorylation
- Contain tyrosine on intracellular domain
- Has the ability to transfer phosphorus to intracellular proteins to activate them, can activate multiple pathways at once
- Regulates cell growth, differentiation and survival
- Proteins require a HS2 domain to bind tyrosine receptors
- Epidermal Growth factor receptor - Has 5 tyrosine per kinase, tyrosine residues phosphorylated are Y992, Y1068, Y1148 and Y1173
1) Ligand binds to the receptor causes them to dimerise and cross link
2) cross linking occurs and the tyrosine on the intracellular domain release phosphorus using ATP
3) 4 proteins can be phosphorylated and activated at a time
Diseases associated with Ion channel related diseases
- Cystic fibrosis caused by malfunctioning ion channel receptor called Conductance regulator (CFTR) and is a genetic disorder that affects 10,000 people in the UK
- The disease affects mucous membranes of the lungs and digestive system
- Normal functioning CFTR channel move chloride ions to the outside of the cell, while a mutant does not, causing sticky mucous to build up
Diseases associated with G protein coupled receptors
- Familial glucocorticoid deficiency is a neonatal/childhood disease exhibiting jaundice, low or undetectable serum cortisol
- Hyperpigmentation, elevated ACTH
- Normal aldosterone
- Problem with the MC2R G protein coupled receptor
Hypothalamic Pituitary Adrenal Axis (HPA Axis)
Hypothalamus –(CRH)–>Anterior Pituatry–(ACTH)–> Adrenal Cortex (M2CR receptor or ACTH receptor)–>Cortisol secretion
-Cortisol released for several hours after experiencing the stressor, excerts negative feedback on the anterior pituitary and hypothalamus to reduce ACTH and CRH hormone in turn reducing cortisol secretion
Diseases associated with Nuclear hormones receptors
- Androgen insensitivity syndrome is an X linked recessive pattern disease causing defects in sexual development
- Patients are genetically (XY) male but have female external characteristics
- The androgen gene is found on the X chromosome
- The androgen receptor sensitivity is dependant on the number of CAG repeats, few repeats causes higher sensitivity and many repeats causes lot sensitivity
Diseases associated with Protein tyrosine kinase receptor
- Cancer, due to PTKR controlling Epidermal Growth Factors Receptors trigger that trigger cell proliferation, survival and differentiation. Can be split into 4 categories, HER1 (EbB1), HER2 (EbB2), HER3 (EbB3) and HER4 (EbB4).
- Malfunction usually causes cancer, activation occurs through tyrosine kinase phosphorylating intracellular substrates. Activates Mitogen Activated Protein Kinase (MAPK)
- MAPK is a chain of protein in cells that communicate a signal from a receptor on cell surface membrane to the DNA in the nucleus of a cell resulting in gene transcription
- Other pathways can also be activated by EGFR
Phospholipase C and Kinases
- Phospholipase C is a class of membrane associated enzymes that cleave phospholipids just before the phosphate group.
- Kinases are enzymes that catalyse transfer of high energy phosphorus from one molecule to another, ATP usually donates the phosphorus
- Addition of phosphorus group can change the shape, overall charge, intra/extracellular electrostatic interactions of a protein
- One activated kinase molecule can phosphorylate thousands of target proteins
