Receptors and signaling Dr. Engisch
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- Function of Na+ channels
- generating and propagating action potentials in excitable cells
- function of K+ channels
- control of excitability and shaping of electrical signals
- Function of Ca++ channels
- neurotransmitter release, muscle contraction and intracellular signalling pathways
- hyperkalemic periodic paralysis
- an Na+ chanenelopathy revealed when extracellular K+ is raised. Channel doesn't inactivate properly and action potential can't develop.
- tetrodotoxin (TTX)
- neurotoxin that is highly specific blocker of voltage-gated Na+ channels. Leads to respiratory paralysis and is found in puffer fish
- local anesthetics- novacain, lidocain
- block voltage gated Na channels in axon and prevent conduction of nerve impulses
- Lamber-eaton Myasthenic Syndrome (LEMS)
- autoimmune disease that impairs calcium influx and reduces transmitter relase at neuromuscular junction resulting in muscle weakness
- halothan
- anestheic that opens the leak K+ channels
- nifedipin and verapamil
- drugs used in the treatment of cardiovascular disease by blocking Ca++ channels
- 3,4 Diaminopyridine
- drug used to treat LEMS by blocking K+ channel and prolongs the action potential
- acetylcholine receptors
- ligand gated channels at neuromuscular junction involved in excitatory neurotransmission
- glutamate receptors
- ligand gated channels at CA3-CA1 hippocampal synapse
- GABA receptors
- ligand gated channels at hippocampal synapses
- Nicotinic acetylcholine receptor
- ligand gated channel at neuromuscular junction that bind Ach and allows Na+ and K+ flux and induces depolarization which increases Ca++ and results in muscle contraction
- hyperpolarized
- a membrane potential which becomes more negative
- depolarized
- a membrane potential which becomes less negative
- acetylcholinesterase
- breaks Ach into acetate and choline and terminates signal
- congenital myasthenic syndrome
- this is a slow channel syndrome present at birth that is caused by mutations on Ach receptors causing weakness, rapid fatigue, and muscle atrophy
- D-Tubocurarine
- competetive inhibitor of Ach that causes paralysis and death by asphyxiation
- Vercoronium, Pancuronium, and Rocuronium
- synthetic chemicals that cause parlaysis by competitively inhibiting Ach receptors. Used in surgical procedures
- α bungarotoxin
- snake toxin that binds competetively and irreversibly to Ach receptors
- Succinycholine
- Ach R agonist that binds and causes depolarization and is used as a muscle relaxant
- Nicotine
- Ach R agonist that binds at same sites as ACh and can cause muscle contraction
- Myasthenia Gravis
- autoimmune neuromuscular disease caused by the destruction of peripheral NACh receptors causing muscle weakness, movement defecit and fatigue
- Picrotoxin
- noncompetetive blocker of GABA
- Benzodiazapine
- anxiolytic drug that increases GABA activity and is used for anxiety disorders and insomnia
- Barbituates
- anticonvulsant and sedative drug that increases GABA activity. Used for epilepsy, anesthesia and anxiety
- Hormone response elements
- DNA sequences where steroid receptor complexes bind and regulate rate of transcription
- Gs
- G-protein that stimulates AC and activates protein kinase A
- Gi
- G-protein that inhibits AC and inhibits protein kinase A
- Gq
- G-protein that is coupled to Phospholipase C which increases DAG, and in turn IP3 and Ca++ and activates protein kinase C
- Cholera toxin
- bacterial toxin that stimulates Gs and causes and excess production of cAMP
- Pertussis Toxin
- bacterial toxin that inhibits Gi and causes excess cAMP
- Sos
- guanine nucleotide exchange factor for Ras that is attracted by Grb2 in the signaling event of tyrosine kinase receptor
- GTPase activating proteint (GAP)
- hydrolyzes GTP and inactivates Ras
- Restriction Point
- the point in G1 when the cell cycle stops being GF dependent
- Oncogene
- a mutated protein of the cell cycle control system that is constituitively activated, Ras, myc, fos, jun
- Tumor supressor gene
- protein that inhibits cell cycle progression- Rb, p53
- Akt pathway
- signaling effect of neurotrophins binding to receptor tyrosine kinase that prevents cell death
- What passes K+ ions but not Na+ or Cl- ions?
- a potassium channel
- changing the cell potential from -80 to 0 mV opens a voltage gated K+ channel. When the channel opens K + ions will flow in which direction
- out of the cell
- a chef preparing puffer fish might find his lips becoming numb because
- tetrodotoxin in the fish inhibits Na+ channels
- If changing the cell potential from -80 to 0 mV opens a voltage gated Ca++ channel, calcium ions will flow in which direction?
- into the cell
- the voltage gated calcium channel pore is formed from:
- a single α subunit consisting of 4 repeated structural units each of which has 6 transmembrane domains
- Voltage gated calcium channels mediate what phase of the cardiac action potential?
- the plateau phase (phase 2)
- Nifedipine and Verapamil block what ion channels to treat cardiovascular disease?
- Calcium channels
- When recording single Na+ channel currents, why are openings only observed at the beginning of a voltage shift to 0 mV
- Na+ channels inactivate after they open.
- Acetylcholine-activated currents at the neuromuscular junction are terminated by
- acetylcholinesterase
- acetylcholine receptor ion channel is opened by
- acetylcholine
- what single channel property is altered in slow channel syndrome?
- open time is increased
- Vecuronium iss used to prepare a patient for surgery because
- It produces paralysis
- the binding of glutamate to NMDA receptors opens an ion channel that passes
- Na+, K+ and Ca++ ions
- why is NMDA current absent at hyperpolarized potentials?
- Mg++ enters the channel and blocks it
- If a cell's resting potential is -80 nV, but it is at -60 mV because of excitatory synaptic activity what happens if a GABA-mediated synaptic current occurs
- the membrane potential will hyperpolarize slightly (become more negative)
- GABA receptors are targets for
- barbituates
- what does ion specificity depend on
- pore size and strength of interaction with pore site
- what is the resting potential of an excitable cell? And are the channels open or closed?
- negative. Closed
- what is the nernst potential for K+
- -105 mV
- what will K+ normally do when the channel is opened?
- move out
- What is the nernst potential fo Na+
- 61 mV
- What will Na+ normally do when the channel is opened?
- move in
- what are the 3 molecular configurations for ion channels
- heteromer, homomer, and a single polypeptide
- which channels mediate fast signalling
- ligand gated
- where are ligand gate channels found
- central and peripheral nervous systems
- what are ligand gate channels called
- ionotropic receptors
- 3 major classes of Glutamate receptors
- Kainate, AMPA, and NMDA
- Which class of receptors have many coregulators
- NMDA Glutamate receptors
- Which class of receptors is rapid desensitization a characteristic of?
- AMPA Glutamate receptors
- When is NMDA current absent
- at hyperpolarized potentials
- Which Glu receptor allows Calcium to pass?
- NMDA Glutamate receptors
- What inhibits NMDA
- zinc
- Examples of blockers of Glutamate receptors
- NBQX, D-AP5. D-AP 7, ketamine, PCP, MK 801
- What is the main inhibitory neurotransmitter in the CNS
- GABA
- What kind of channel are GABA- receptors?
- Chloride
- What does GABA receptor openings cause to membrane potential?
- hyperpolarization
- What do GABA receptors have binding sites for
- barbituates, benzodiazepines, and potentiators
- Steroids bind to⬦
- intracellular receptors that affect gene transcription
- G-protein coupled receptors are made up of
- a single subunit with 7 transmembrane domains
- Gq is a heterotrimeric G protein that couples to
- phospholipase C. It stimulates PLC, increases DAG, increases IP3, increases intracellular calcium and activates PKC
- Once cAMP is generated its signaling effects are terminated rapidly because it is destroyed by ⬦
- phosphodiesterase
- IP3 receptors are primarily located ⬦
- in the membrane of the ER
- Albuterol, a bronchodilator used to treat asthma, acts at what G-protein coupled receptor
- beta adrenergic receptor, as an agonist
- Cholera toxin kills by dehydrating the body through massive diarrhea and vomiting. It does this by attacking the cells of the uppers section of the small intestine and⬦
- stimulating Gs, causing an excess production of cAMP
- Ligand binding to receptors eventually leads to loss of receptors. This is mediated by what process?
- phosphorylation of GRK, binding of β-arrestin to the phosphorylated sites, and recruitment of β-arrestin of endocytosis proteins such as clathrin
- The insulin receptor is a
- tyrosine kinase receptor
- the unliganded epidermal growth factor tyrosine kinase receptor is made of a
- a single subunit with 1 transmembrane domain
- Activation of Ras leads to the following cascade
- activation of Raf, phosphorylation and activation of MAP kinase kinase, phosphorylation and activation of MAP kinase
- Growth factor binding to tyrosine kinase receptors stimulates progression of the cell cycle at what stage
- G1
- The primary cyclin that responds to growth factor stimulation is
- Cyclin D
- PI3 kinase catalyzes
- phosphorylation of PIP2 to form PIP3
- What are the 4 major receptor signalling classes?
- steroid, g-protein coupled, receptor tyrosine kinases and guanylate cyclase nitric oxide signaling
- Family I steroid receptor signaling
- steroid enters the PM, binds to receptor and releases heat shock proteins, enter the nucleus and binds to DNA as dimer to up or downregulate transcription of mRNA
- Family II steroid receptor signaling
- steroids enters the PM, enters the nucleus and binds to receptor, complex binds to DNA as hetero or homo-dimer to up or downregulate transcription
- What facilitate the binding of steroid receptors to DNA sequences?
- zinc finger
- Steroid-steroid receptor examples
- androgens and vitamin D
- What do androgens regulate?
- male sexual differentiation and pubertal changes
- where can HREs of androgens be found
- in laryngeal myosin, prostate specific antigen
- What can agonists of androgens treat?
- hypogonadism
- what do antagonists of androgens treat?
- prostate cancer
- What does Vitamin D regulate?
- bone mineralization, Ca++ and PO4 homeostatis
- What causes rickets
- a deficiency in vitamin D
- Where are vitamin d HRE's?
- calbindin
- What does the binding of a ligand to G-protein couple receptor do?
- facilitates the exchange of GTP for GDP and the α and βγ to dissociate
- How is a G-protein couple receptor signal terminated
- GTP is hydrolyzed to GDP and the α subunit dissociates
- How do cells respond to persistent stimulation by a drug?
- by decreasing the number of receptors available to respond to a drug
- 3 steps of developing tolerance
- desensitization, internalization and down regulation
- What does the binding of a ligand to a receptor tyrosine kinase cause?
- dimerization
- What is the binding site for Grb2
- the P-tyrosines of the receptor tyrosine kinase
- How does GTP-Ras stimulate the MAP kinase cascade?
- interacting with Raf kinase (Map kinase kinase kinase)
- What does MAP kinase lead to?
- early gene transcription and eventual activation of cyclins to stimulate cell division
- What happens to cells deprived of Growth Factor
- arrest at G0
- Growth factors effect on cyclin D
- 1) induce transcription 2) stabilize 3) promote translocation to nucleus 4) promote assembly with Cdk 4 and 6
- dephosphorylated Retinoblastoma protein
- binds regulatory protein that favor proliferation
- phosphorylated Rb
- releases proteins so the cell proliferate
- What causes unregulated proliferation
- expression of oncogene, loss of tumor supressor gene, Growth factors always activated
- Functions of neurotrophin
- stimulate axonal and dendritic outgrowth and synapse formation; potentiates synaptic function; and promotes cell migration
- Where do neurotrophins bind
- receptor tyrosine kinases, with 3 signaling effects