Ion Channels Flashcards
What percentage of drugs target ion channels?
18%
How many genes encode for pottasium channels subunits in the human genome?
over 70
How do pottasium channels regulate cell excitability through different modalities?
Frequency and shape of action potentials.
Secretion of hormones.
Secretion of neurotransmitters.
Membrane potential.
How many transmembrane domains do pottassium channels have in an alpha subunit?
6
Where is the pore on a pottassium channel?
between the S5 and S6 transmembrane channel of the 4 alpha subunits
What is the key region in the pottassium channel for response to voltage?
S4 because its positively charged
“voltage sensing domain”
What does a homomeric pottassium channel contain?
all subunits from same family
What does a heteromeric pottassium channel contain?
subunits from different families
What does minoxidil do?
What does this do?
And what does it indicate?
opens K+ channels
Causes hyperpolarisation in smooth muscle cells, muscle relaxation and hence vasodilation.
Indication: Can be used in the treat of hypertension in combination with a diuretic and β adrenoreceptor blocker
What are sodium channels?
Sodium channels are voltage-gated sodium-selective ion channels present in the membrane of most excitable cells.
What comprises a sodium channel?
Sodium channels comprise of one pore-forming α subunit, which may be associated with either one or two β subunits.
How many genes encode for a sodium channel?
at least 10
Which subunit is voltage sensing in a sodium channel?
S4
Where is the pore in a sodium channel?
Between S5 and S6
What does Lidocaine do?
What does this do?
And what does it indicate?
Lidocaine: blocks voltage-gated sodium channels (Nav1.5, Nav1.7, Nav1.9).
Primary target is Nav1.5 which is the main cardiac sodium channel.
Indication: ventricular arrhythmias, especially after myocardial infarction. In addition to local anaesthesia.
Explain what Nav1.5 means
Na = sodium v= voltage 1 = sub family 5 = subtype
What are calcium channels?
Calcium (Ca2+) channels are voltage-gated ion channels present in the membrane of most excitable cells.
What do calcium channels form?
Ca2+ channels form hetero-oligomeric complexes. The α1 subunit is pore-forming and provides the extracellular binding site(s) for practically all agonists and antagonists.
How many families of calcium channels exist?
What are they?
Three families exist : (1) the high-voltage activated dihydropyridine-sensitive (L-type, CaV1.x) channels; (2) the high-voltage activated dihydropyridine-insensitive (CaV2.x) channels and (3) the low-voltage-activated (T-type, CaV3.x) channels.
gabapentin and pregabalin are drugs what subunits of calcium channels allow them to bind?
The α2–δ1 and α2–δ2 subunits bind gabapentin and pregabalin
How many domains do Calcium channels have?
4
How many transmembrane subunits do the calcium channel domains have?
6
What subunits make up a high voltage activated channel?
gamma
beta
alpha 1
alpha 2 delta
What subunits make up a low voltage activated channel?
alpha 1
What does verapamil do?
What does this do?
And what does it indicate?
Verapamil: blocks voltage-gated calcium channels (L-type)
Blocks calcium influx in myocardial and vascular smooth muscle cells. Leads to a reduction in cardiac and VSM contraction bringing about a dilation in coronary and systemic arteries.
Indication: supraventricular arrhythmias, angina, hypertension (dose and preparation dependent)
What are the channelopathies for epilepsy?
Ca2+ channels
K+ channels
NA+ channels
What are the channelopathies for diabetes?
K+ channels
K ATP channels
What are the channelopathies for ataxia?
K+ channels
Ca2+ channels
What are the channelopathies for pain?
Na+ channels
Ca2+ channels
Why are ligand gated channels sometimes referred to as ionotropic receptors
Link ligand binding to an ionic flux.
What is the usual structure for a ligand gated ion channel?
Heteromeric (with 4-5 subunits)
What is the gated ion for the receptor class: Nicotinic ACh?
Is its cellular effect excitatory or a depressant?
Na+
excitatory
What is the gated ion for the receptor class: Glutamate (ionotropic)?
Is its cellular effect excitatory or a inhibitory?
Na+
Excitatory
What is the gated ion for the receptor class: 5HT3 (seratonin)?
Is its cellular effect excitatory or a inhibitory?
Na+
excitatory
What is the gated ion for the receptor class: Glycine?
Is its cellular effect excitatory or a inhibitory?
Cl-
Inhibitory
What is the gated ion for the receptor class: GABA (A)?
Is its cellular effect excitatory or a inhibitory?
Cl-
inhibitory
What are the gated ions for the receptor class: P2X (ATP receptors)?
Is its cellular effect excitatory or a inhibitory?
Na+ K+ Ca2+ Cl-
excitatory or inhibitory
What are ligand gated ion channels?
Ligand-gated ion channels (LGICs) are integral membrane proteins that contain a pore which allows the regulated flow of selected ions across the plasma membrane.
What is an ion flux in a ligand gated channel and how is it caused?
Ion flux is passive and driven by the electrochemical gradient for the permeant ions. These channels are opened by ligand binding that triggers a conformational change that results in the ‘conducting’ state.
What is the time scale of a ligand gated ion channel mediated synaptic transmission?
LGICs mediate fast synaptic transmission, on a millisecond time scale, in the nervous system and at the somatic neuromuscular junction.
Why are ligand gated ion channels also suggested to have other functions?
Their presence of non-excitable cells
How many transmembrane domains does each subunite of a nicotinic Acetylcholine receptor have?
4
Which transmembrane domain from each subunit of a nicotinic Acetylcholine receptor lines the pore?
TM2
How was the structure of a nicotinic Acetylcholine receptor solved?
X-ray crystallography
For a nicotinic Acetylcholine receptor which direction do sodium ions flow?
What do they do?
along conc gradient
Causes depolarisation of cell
Muscle: contraction
Neuron: increases probability of neurone firing action potential
What is the time scale of a nicotinic Acetylcholine receptor within ligand binding?
milliseconds
What changes the acetylcholine receptors type?
Depending on the combination of subunits
Where are the usual ligand binding sites on ligand gated ion channels?
alpha subunits
What are the exceptions to the ligand gated ion channel rules?
glutamate
P2X for ATP
Why do glutamate receptors break the ligand gated ion channel rules?
M2 is not a fully transmembrane domain extracellular NH2 Intracellular COOH has extracellular ligand binding domains 4 subunits creating a channel
Why do P2X for ATP receptors break the ligand gated ion channel rules?
Only 2 transmembrane domains
Intracellular C and N terminus
extracellular ligand binding domain
3 subunits making a channel
What does Succinylcholine do?
What does this do?
And what does it indicate?
Succinylcholine: full agonist of the nACh receptor
Mimics the effects of ACh but is not subject to breakdown by AChE.
Indication: neuromuscular blockade (short duration) for surgery
What does Memantine do?
What does this do?
And what does it indicate?
Memantine: non-competitive NMDA receptor antagonist
Blocks overstimulation of NMDA receptors evident in Alzheimer’s disease.
Indication: moderate to severe dementia of the Alzheimer’s type.
What does Granisteron do?
What does this do?
And what does it indicate?
Granisteron: 5-HT3 antagonist
5-HT mediates synaptic transmission to the medullary vomiting centre and area postrema.
Indication: Nausea and vomiting induced by cytotoxic chemotherapy or radiotherapy (oral or transdermal). Postoperative nausea and vomiting (intravenous).
What does Diazepam do?
What does this do?
And what does it indicate?
Diazepam: full agonist of the GABAA receptor
Potentiates GABA (inhibitory) activity, increasing Cl- influx.
Indication: short-term use in anxiety or insomnia, life-threatening acute drug-induced dystonic reactions, adjunct in acute alcohol withdrawal, status epilepticus, febrile convulsions, muscle spasm.
What does Ivermectin do?
What does this do?
And what does it indicate?
Ivermectin: irreversible agonist of the glycine receptor
Activates glycine receptor, hyperpolarisation of cells (influx of Cl-).
Indication: For the treatment of intestinal (i.e., nondisseminated) strongyloidiasis due to the nematode parasite Strongyloides stercoralis. Also for the treatment of onchocerciasis (river blindness) due to the nematode parasite Onchocerca volvulus. Can be used to treat scabies caused by Sarcoptes scabiei.
What does Suramin do?
What does this do?
And what does it indicate?
Suramin: broad spectrum P2X receptor antagonist.
Blocks ATP activation of P2X receptors, leading to a change in intracellular Ca2+.
Indication: parasite infections.
