Intro The Cell Regulation Flashcards
Mechanisms that cells influence other cells.
1) Electrical
o Allow spread of electrical activity, through low resistance gap junctions
o Endothelial cells, cardiac myocytes, epithelial cells
2) Chemical synapses
oRelease of a chemical released from one cell which influences another cell
oFormation, synthesis and then release from chemicals in neurones.
oDigestive enzymes (like neurotransmitters – created, packaged in cells and then released in calcium dependent manner
o Drugs themselves have no effect – need to interact with something to have an effect
Key components involved in cellular physiology
- Cells made up of lipid bilayer – charged molecules can’t get through
- Cellular activity – very complex and multi factorial.
- Many ways cellular activity controlled - depends on type, how active, proportion and how they are influenced by intracellular signals.
- Major targets for drug action
How receptors, ion channels and exchangers / pumps function.
Receptors are proteins that bind chemicals in very specific manner and respond to them:
• Ligand gated ion channels - superfast receptors (1/1000th of a second)
• G protein coupled – slightly slower than ligand-gated, but faster than tyrosine kinase
• Tyrosine kinase linked slightly slower then G-protein.
• Steroidal/Nuclear receptor – found in cytosol. When specific agonist binds, they translocate to the nucleus and later are involved in gene transcription.
Ion channels
• Proteins that create an aqueous pathway through fatty lipid membrane bilayer.
• Allows charged ions to pass through the membrane in/out depending on ionic gradients.
• Ion channels create pathway which has to form a barrel-like structure so ions can pass through (by one single protein, or 2/4 proteins coming together).
• Very good at selecting which ion to let through - functions as molecular sieve.
• 72 K+ channel genes – but lots of complexity about their assembly. Most K+ channels will allow heteromeric assembly (differently assembled).
• Ion channels can be secreted by how they are activated and ion that goes through them
How a single signal (chemical) can have different effects on different cells.
Same molecule can have different effects on the body
•Acetylcholine= Main transmitter in parasympathetic system
-Increase saliva production from salivary gland
-Cause slowing of heart rate, and reduce force of contraction in heart
-contraction of skeletal muscle.
-Contract bowel smooth muscle -Relax arterial smooth muscle
-Type of receptor, and cell environment determines role of transmitter.
Different types of signalling
o Paracrine: Release of chemicals from one cell which influences cells in locality
o Autocrine: Cell release chemical which influences its own activity.
o Endocrine: Chemical released into the blood stream and interacts with receptor to produce cellular response downstream
o Synaptic: More focussed released of chemical from a neurone from discrete packages, released into a synapse (small distance from target cell), diffuse short distance interact with receptors and get cellular response.
How is cellular activity regulated?
1) Receptors Main way chemical release from one cell influences another cell • Ligand Gated • G-protein coupled • Tyrosine Kinase Linked • Nuclear
2) Ion channels Allow movement of ions through the membrane Ionic gradients set up by transporters • Voltage gated • Ligand gated
3) Transporter Can bring in ions, other molecules such as glucose, amino acids • Exchangers • Symporters • Antiporters
4) Enzymes
Alter cellular activity
Voltage-gated channels
- These channels opened by membrane depolarisation
- All cells live with membrane potential of -60mV, some more or less.
- Drug companies target these channels to produce beneficial effects.
Voltage gated Na+ channels
- Only allows Na+ into the cell down it’s concentration gradient.
- If membrane potential becomes less negative – depolarisation, Na+ channels open and Na+ enters the cells
- Stimulation of neurones occurs through cyclical opening of voltage gated ion channels. Block these, there’ll be pain relief. Local anaesthetics and molecular target is to block voltage gated sodium channels.
Voltage gated Ca2+ channels
• Targeted pharmaceutically – block these, less Ca2+ influx. Influx of Ca2+ in muscle cells - get a contraction. Agents that block these channels, will prevent contraction and so are good relaxants of vascular smooth muscles for patients with high BP.
What are the uses for voltage gate channels?
Na+: local anaesthetics eg lignocaine or procainamide
Ca2+: dihydropyridines eg nifedipine and anti-hypertensives
K+ and Cl-: anti-arrhythmic agents eg vernakalant
Ligand-gated channels
- Chemical binds to binding site and open ionic pathway
- Valium – bind to ion channels, stabilise it being open and calming neurones down
- Ca2+ activated K+ channel – Ca2+ activates another ion channel.
- So, if Ca2+ channel is bringing in calcium, which is close to potassium channel, it calms activity down and keep things brief.
- Ca2+ influx -> cardiac myocyte/ muscles cell/neurone starts to get excited. But entry of Ca2+ stimulates these ion channels, so opening K+ channel, calms it down
- So, the level of excitation is brief, explosive and controlled.
• Ion channels activated by intracellular signalling molecules such as cAMP or cGMP.
• All kinases are stimulated by these
E.g. Cystic fibrosis ion channel CFTR -> Cl- channel found in epithelia and digestive tracts, which are increased by cAMP dependent kinases.
• Kinase – something which phosphorylates.
• Phosphorylate chloride channel to get Cl- movements.
• Ion channels differ in different cell types.
E.g. Cardiac myocytes in atria have different complement of ion channels to cardiac myocytes in ventricles. Drug companies can then use this difference to create drugs that only target arrhythmias in atria leaving ventricles alone.
Transporters
o Proteins that move ions in or out of the cell, that sets up the gradient that allows ion movement through an ion channel.
o Exchangers – one molecule is exchanged for another one
• E.g.) Na/K ATPase (ATP consumed in process of something happening). In most of our cells, potassium is controlled largely by Na+/K+ ATPase.
• Na+/K+ ATPase inhibited by drugs such as Ouabain and Digoxin.
• Prescribed for heart failure, knowns as cardiac glycosides and give heart a boost. Molecular target is Na+/K+ ATPase.
Digoxin boosts cardiac contraction. Binds to Na+/K+ ATPase pump.
Inhibiting Na+/K+ ATPase, more Na+ builds up in cardiac myocyte. Na+/Ca2+ calcium exchanger goes the other way. and so, exchanger goes the other way – bring Ca2+ in. More calcium, more contraction. – extra contractions on cardiac myocyte. (re-listen at 37 mins)
• Cl/HCO3 exchanger
Cotransporters
1) Symporters – come in together
2) Antiporter opposite directions but not exchange manner
E.g.) Na+ accumulated in kidneys to set up osmotic gradient so latter part of kidney is water permeable, it flows down osmotic gradient. Most of Na+ accumulation by NaCl transporter in Distil Convoluted Tubule and Na/K/Cl transporter in ascending limb of loop of Henle.
Targeted these proteins for therapeutic benefit.
Heart failure usually put on diuretics – actively block NA+ accumulation mechanisms. No accumulate of NA, no osmotic gradient, and so no water coming out of nephron and so excrete it out.
Mechanisms of maintaining calcium level in the cytoplasm
Role of Calcium o Produces contraction o Stimulates some enzymes o Causes cellular apoptosis However, if calcium levels stay too high, various enzymes are activated, get DNA damage, and cells membrane start to deform, and start to blow up by apoptosis - so very precise control of calcium
Regulated by the cardiac myocyte, by Na+/Ca2+ exchange.
Ca2+ leaves cell in response to Na+ coming in
Ca2+ pumps
Consume ATP to drive it, Ca2+ pumped out against its gradient.
Pump in ER, that stores Ca2+, so Ca2+ gets pumped into the stores
Esp. muscle cells have internal calcium stores
Mitochondria generates ATP but also a big calcium store.
Too much calcium in mitochondria – mitochondrial damage, ATP generation and aerobic activity affected, damage to mitochondria and cell death.
Balance crucial for maintaining cellular activity
