rec- structure and signalling (main focus on proteins) Flashcards
importance of ca2+ in the cytoplasm (7 answers, get main 4)
- cell signalling- binding of another molecule to receptor may cause ion cascade
- muscle contraction- AP along membrane, release of stored ca2+= binding to contractile PROTEINS
- neurotransmitter release in presynapse
- cell communication
- gene expression and regulation
- cell cycle
- apoptosis
structure of TMPs
2+ alpha-helicies
2-6 subunits that surround the pore (usually w/ exceptions like ammonia (?) and Chlorine)
2 reasons for ion selectivity
size of the filter
and AMINO ACID linings of the pore
AMINO ACID selectivity in pores
Size- smaller molecules dont have to interact with the aa’s
aa’s on negatively charged chains will react positively with positively charged ions, but repel the negatively charged ones
which side of the TM is tighter, and therefore creating a ‘gate’
cyctoplasmic side
difference between the groups of ions, Na+, K+ and Ca2+
Na+ and K+ create APs in excitable cells
Ca2+ transported into cytoplasm where 2nd messenger elicits cell response- cascade etc
3 differences to a simple ion channel
- additional helices S1 and S4- form a separate ‘voltage sensing domain’ lateral to subunits
- Large polypeptide extends into cytoplasm
- plugging mechanism
TRPs sense what stimuli= 2
physical stimuli and chemical
2 types of ligand gated ion channels=
intracellular ligand and extracellular ligands
example of how ligand gated ions channels can cause seizures?
mutation in nAChR causing autosomal dominant nocturnal frontal lobe epilepsy
how the nAChR work and what goes wrong
- ACh conc depends on use of use-dependent potention
the delay in the rising phase of the mutant ACh response= caused by slow unblocking of the CLOSED mutant rec
Glutamate acts in what part of the body
the brain, as the main neurotransmitter
uniqueness of the NMDA-glutamate receptor
role in synaptic plasticity, learning and memory
structure of the NMDA-glutamate receptor- and its importance
voltage dependence activation
high calcium permeability
involvement in long-term potentiation and long term depression- synaptic plasticity
regulation and specificity of the Glut-NMDA rec
VOLTAGE DEPENDENCE AND THE MG2+ BLOCKADE
NMDA receptors are unique in that they require both GLUTAMATE BINDING and POSTSYNAPTIC MEMBRANE DEPOLARISATION to function.
When the membrane is at resting potential, a magnesium ion (Mg2+) blocks the ion channel pore of the NMDA receptor. Depolarization of the membrane displaces the Mg2+ ion, allowing ions to flow through the open channel.
disfunction of the GLUT-NMDA rec
contribution to human disease and loss of function
difference between the 3- 2 Glutamate receptors
AMPA, NMDA and Kainate
AMPA- mediate FAST excitatory synaptic transmission in CNS
NMDA- slower than other isoforms, inv in learning and memory
Kainate- Similar to AMPA but a lesser role at synapses
linked to schizophrenia, depression and huntingtons
RNA editing/ splicing/ transport in the AMPA rec-
used to 1. add subunit diversity- like allowing increased calcium ion permeability of the complex
2. synaptic plasticity- how the synapse alters the strength of the activity- strengthen or weaken
3. disease and neurological disorders- dysregulation of RNA processing in AMPA rec- linked to epilepsy and neurodegenerative disorders
example of dysfunction of glutamate receptors- NMDA- overstimulation of NMDAR
= neuronal death= exitotoxicity
How the overstimulation of the NMDAR leads to excitotoxicty= neuronal death
from Ca2+
increased Ca2+ influx leads to a signalling cascade ultimately leading to neuronal cell death
after the glutamate release presynaptically, then the NMDAR activation, and Calcium influx
1. intracellular signalling cascades= cascade leading to activation of enzymes like phospholipases, proteases and kinase- can damage intracell structures etc
2. mito dysfunction- distrupt mitochondrial function= decrease in ATP production and release of pro-apoptotic factors
etc
dysfunction of RNA modification= leading to pathologic conditions
3 examples of the AMPA2 activity
- downreg of GluA2 Q/R editing in motor neurones of ALS patients = increase of Ca2+ permeable AMPAR causes damage to glutamate excitotoxicity
- In glioblastoma, decreased ADAR2 activity correlated w/ increased malignancy
increase in Ca2+= Akt pathway promoting proliferation and tumourigenesis
P2X receptors- trimeric
structure, binding + site
3 subunits w/ 2 TM helices
3 ATP molecules needed to open channel
IIII- added info, large extracellular domain- where the ATP binding is
, widely expressed, and P2X1-7 subtypes of subunits
Importance of the P2XR’s
Neurotransmission- activation of P2XR in neurones > release of neurotransmitters and modulation of neuronal activity
Pain perception- in sensory neurones- lead to transmission to CNS
Immune response- on immune cells, can regulate immune cell activation, inflammation and cytokine release
Cardiovascular sys- in smooth muscle cells
Pharmacology- targets of drug development, both agonist and antagonists- been developed to modulate P2XR activity
-pain management, inflammation control etc
