Ion Channels and Pain Flashcards
5 receptor types
Lipid-soluble ligand Enzymatic reaction Tyrosine Kinase activation Ion channel activation G protein-coupled receptor
Ion channels provide a _____ route for ions through _____ _____ membranes
Permeable
Hydrophobic lipid
Ion channels consist of ____ folded into ________
amino acids
complex structures
Ion channels are made from 3-6 similar ______ or ______
proteins
structural subunits
Can ion channels be selective to specific ions? non-selective?
Yes
Yes
Definition of gating
open and close in response to specific chemical, electrical or mechanical signals
Ion channels conduct ions across _____________
plasma membrane
Ion channels regulate ________ ________ of cells
membrane potential
5 types on ion channels
Resting K+ channel Voltage-gated channel Ligand-gated channel Signal-gated channel Mechanically-gated channel
Ions that cross through voltage-gated channels?
Na+, K+, Ca2+, Cl-
How many transmembrane segments are in the voltage-gated ion channels?
6
Voltage-gated ion channels open in response to changes in what?
membrane potential
2 domains in voltage-gated ion channels?
Voltage sensor domain (S1-4) Pore Domain (S5-6)
3 major superfamilies on Ligand-Gated Ion channels?
Cys-Loop Receptors
Ionotropic Glutamate Receptors
P2X Receptors
Ligand-Gated Ion Channels : transmembrane domains are important for? (2)
pore formation
ion selectivity
Ligand-Gated Ion Channels : what is important for ligand binding? (determines which ligand can bind to it)
extracellular domains
Extracellular domain of Cys-Loop receptors?
Disulfide bridges of cysteine residues
Extracellular domain of Ionotropic Glutamate receptors?
Ligand binding domain (segment and 2)
N-terminal domain
Two ways a cell can sense a mechanical stimuli?
Direct gating by physical opening of channel
Indirect by activation of GPCR then opening of TRP channels
What happens in regard to action potential when activating a ligand-gated ion channel?
Opening, Na+ influx, nerve depolarisation
Effect of a mild mechanical stimulation
Opening of only a few ion channels, but firing isn’t highly activated, relatively few action potentials
Effect of noxious mechanical stimulation
Many ion channels open, nerve firing probability increased and multiple action potentials can be generated which means more firing of the nerves
Effect of noxious mechanical stimulation
Many ion channels open, nerve firing probability increased and multiple action potentials can be generated which means more firing of the nerves
Resting membrane potential value?
-70mV
Which complex helps the transport of cations and anions to normalize the membrane potential?
Na+/K+ exchange pump
Concentration gradients of Na+ and K+ in extracellular and intracellular?
Extracellular:
K + 4.5 mM
Na+ 145 mM
Intracellular
K+ 120 mM
Na+ 15 mM
What causes sodium to enter channel? what happens to action potential?
stimulus
depolarization (spike in voltage)
When sodium leave the cell and ion channel closes, what happens to action potential? What does this do to ADP-ATP?
repolarization
Exchange ATP for ADP
Example of Cys-Loop Channel?
Nicotinic Ach Receptor
Nicotinic Ach Receptor : subunits?
two alpha
one beta
one gamma
one delta
Nicotinic Ach Receptor requires how many Ach molecules for activation? Which ion influxes once the pore opens
2
Na+
Nicotinic Ach Receptor functions? (4)
- Skeletal muscle contraction
- Smooth muscle relaxation
- Inhibits cardiac muscle contraction
- Nerve depolarization
What dictates the location and pharmacology of Nicotinic Ach Receptors?
Subunit composition
What causes depolarizing blockade? (Nicotinic Ach Receptor)
Excess Ach and Nicotinic Receptor Agonists
Depolarizing blockade : what are the effects of continuous activation of nicotinic receptors?
Muscle excitation and fasiculations in myocytes and then flaccid paralysis
Depolarizing blockade : what are the effects of prolonged agonist bound nAchRs?
neuron desensitization
Depolarizing blockade : what are the effects of continuously depolarized membrane?
Affects inactivation of voltage-gated sodium channels (nerve less likely to fire)
nAch Receptors located where?
DRG
Dorsal horn of spinal cord
Ach sensitizes about 50% of ___ fibres for heat but not ________ pain
C
mechanical
Analgesics for nAch Receptors and Pain? (4)
They inhibit what? (2)
Botulinum toxin, alpha-7 blockers, epibatidine, nicotine
Inhibits inflammatory neuropeptide and cytokine release
GABAARs Cys-Loop Receptor : what type of receptor? allows passage of what ion?
Inhibitory (hyperpolarization)
Cl-
Composition of GABAAR?
Heteropentameter with variable subunits
GABAARs activated by what?
GABA
GABAARs are found where?
Dorsal horn of spinal cord
Roles of GABAAR? (2)
Inhibits pain transmission by hyperpolarizing second order neurons
Inhibits substance P release form primary afferent neurons
Which drugs potentiate GABA-mediated synaptic inhibition? (2)
Benzodiazepines
Barbiturates
GABA binds where on GABAAR?
alpha-beta interface
Benzodiazepines binds where on GABAAR?
alpha-gamma subunit interface (allosteric binding site)
Barbiturates interacts with what on GABAAR?
Pockets in the transmembrane domain
Acute pain?
warning system for harmful stimuli
chronic pain lasts more than _____ months and it is __________
3
maladaptive
the Nervous system can change in response to pain because it is _______
plastic