28th Nov - Drug action at ion channels Flashcards
Describe the structure of Kir6
2 TM domains in each subunit
2 Kir6 subunits form the pore forming domain of KATP channels
Kir6 has an ATP binding site
Kir6 are not voltage sensitive
What is Kir6?
An inwardly rectifying potassium channel which form the pore forming subunits of Katp channels
Molecularly what causes inward rectifying currents in an inward rectifying potassium channel?
Cytoplasmic long chain aliphatic compounds with more than one amine group are attracted the intracellular side of the channel, blocking the channel creating the characteristic I/V curve
What is the function of the sulphonylurea receptor subunits?
They are the regulatory subunits of Katp which bind sulphonylureas
Give an example of a sulphonylurea
glibenclamide
tolbutamine
What binds to the sulphonylurea receptor subunits of the Katp channel?
Sulfonylureas
Meglinitides
Outline the role of Katp channels in insulin secretion
Low metabolism –> Increase in MgADP and Decrease in ATP –> Katp channels open and calcium channels close –> hyperpolarisation
High glucose –> high metabolism –> Increase in atp and decrease in MgADP –> Katp channels close and potassium channels open –> depolarisation –> insulin release
How do sulfonylureas stimulate insulin release?
They inhibit the Katp channel causing depolarisation and insulin release
What is the sulfonylurea drug of choice?
Tolbutamide
What is permanent neonatal diabetes mellitus?
Diabetes diagnosed int he first 6 months of life that does not resolve over time caused by a mutation in KCNJ11 (Kir 6.2) or ABCC8 (Sur1) mutation
What are the two different mutations in KCNJ11 in permanent neonatal diabetes mellitus and what are their clinical effects?
Mild disease = R201H/C mutation in the ATP binding site
- Reduces ATP sensitivity of the Katp channel
- Causes the channel to favour the open state leading to a reduction in insulin release
- Will respond to sulfonylureas
Severe disease = V59G/M, Q52R mutation in the gating region
- Increases the open probability independent of ATP
- Causes hyperpolarisation of the cell
- Not treatable with sulphonylureas
- Also causes developmental delay epilepsy
What are the effects of a mutation in SUR1 in permanent neonatal diabetes mellitus?
Overactive channels
Mutant channel does not does in response to high ATP
Sulphonylureas are not always effective, individual molecular diagnosis is required
What is hyperinsulinemic hypoglycemia of infancy?
Congenital hyperinsulinism
Kir 6.2 mutations and Sur1 mutations cause loss of Katp channel function
Describe the two classes of hyperinsulinemic hypoglycemia?
Class 1
- Protein trafficking deficit
- Protein not present at the membrane
- very severe
Class 2
- Functional mutation, usually of SUR1
- Channels remain closed
- Mild
What is the clinical use of drugs targeted to open Katp channels in the vascular smooth muscle?
To treat hypertension
