ion channel disorder

Question 1

what is the importance of plasma membrane channels?

Answer 1

play key roles in membrane excitability, potential and ion homeostasis

Question 2

what components form part of the calcium ‘‘off mechanisms’’

Answer 2

SOCE and SERCA act to refill the ER store

PMCA to help with calcium efflux

Question 3

does SOCE occur in all cells?

Answer 3

generally SOCE occurs in non-excitable cells like PAC whilst excitable cells have voltage/ligand gated channels which facilitate calcium entry (L-type channel)

Question 4

name some intracellular calcium channels

Answer 4

ER - ip3R and ryR

endolysosmal membrane - two pore calcium channels are ligand gated cationic intracellular channels but non-specific for calcium

Question 5

what second messengers is used in PAC calcium signaling? What is the stimulus for this?

Answer 5

PLC used to generate IP3 and its stimulus is Ach acting on musc3R

ADP-RC creates NAADP and cADPR to stimulate RyR
its stimulus is CCK acting on its plasma membrane receptor

Question 6

what does the PMCA do?

Answer 6

Plama membrane Calcium ATPase acts to remove excess cytsolic calcium and remove by pumping it OUT of the cell

Question 7

if apoptosis is a ATP dependent process why is there so much necrosis in AP?

Answer 7

in AP there is insuffient ATP to drive apoptosis so cells by necrosis instead

Question 8

how is IP3R implicated in channelopathy?

Answer 8

overstimulation/GOF leads to pathology (calcium overload)

Question 9

how can calmodulin influence calcium signallin

Answer 9

its a intracellular calcium sensor so can bind with high affinity to calcium and activate PMCA and inhibit IP3r

acts to reduce calcium

Question 10

what is the biological importance of Ryr?

Answer 10

important for skeletal muscle and cardiac contraction

Question 11

what is the biological importance of IP3R?

Answer 11

development
fertilisation
neuronal plasticity and olfaction

Question 12

what can sustained calcium rise lead to? (in PAC)

Answer 12

mitch dysfunction + ATP depletion

premature zymogen activation and autodigestion

local inflammation from calcineurin activation???

Question 13

why is it hard to target intracellular receptors than plasma membrane receptors to treat AP?

Answer 13

drug will need to be able to pass the lipid bilayer and specificially target the receptor. should not accumulate to toxic levels and so should be able to be metabolised

so much easier to target plasma membrane

Question 14

what proteins are involved in store operated calcium entry?

Answer 14

STIM1/2 - long calcium sensor or ER and able to oligomerise translocate to plasma membrane

ORAI - on plasma membrane and subunit of CRACalcium channel

Question 15

just to clarify what is orai?

Answer 15

ORAI is the gene and the protein family make up the CRAC channel

Question 16

what is a concern about using CRAC channel blockers?

Answer 16

stim and orai are ubiquitously expressed across a range of tissues so global effects could be observed

(although not actually true) as other tissues have voltage gated channels/other means of calcium entry

Question 17

what is a concern about using CRAC blockers long term?

Answer 17

SOCE is major route of T-cell activation so long term use would mean a reduced cell mediated immune response

Question 18

why is childhood acute lymphoblastic leukemia associate with AP

Answer 18

treatment of ALL uses L-aspariginase

but ASP has emerged as an inducer of AP by creating sustained calcium oscilation

Question 19

what is the role of PAR-2 in apsaraginase associated AP?

Answer 19

this is a plasma membrane receptor that is actvated by ASP and also trypsin

leads to second messenger PLC and calcium oscillation

Question 20

why has no PAR2 blocker been created?

Answer 20

difficult as it has a unique structure and distinct conformational changes

so hard to target with specificity

Question 21

how can galactose be useful therapy for AP?

Answer 21

Bile acid and alcohol inhibit hexokinase so galactose can restore ATP production by bypassing hexokinase and enter Krebs cycle with ease

has been shown to have protective role in induced AP mouse models

Question 22

how is covid 19 associated with AP?

Answer 22

seems the spike protein can activate pancreatic stellate cells

stellate produce cytokines IL-18 activating macrophage = local inflammation