C1 - Calcium release channels


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Calcium release channels experiments

Ταίριασμα του κειμένου (κλικ και σύρετε)   


Ταίριασμα του κειμένου

Sitsapesan & Colleagues aim

Sitsapesan & Colleagues methods

Sitsapesan & Colleagues findings

Kermode aim

Kermode methods

Kermode findings

Chen aim

Chen methods

Chen findings

Yan aim

Yan methods

Yan findings

Gillespie aim

Gillespie methods

Gillespie findings

Κάντε κλικ και σύρετε

FKBP12-> activates RyR2, inhibits RyR1. FKBP12.6-> activates RyR1, partial agonist @ RyR2. Three residues found to determine these differences.

Proposed the nature of the countercurrent for RyR

describe regulation of native RyR by ATP/ADP

Determine near-atomic structure of RyR1

site directed mutagenesis @ C-terminus -ive residues. in vivo het knock-in of mutation found to abolish luminal sensing.

A countercurrent is necessary to stop changes in Vm that would be inhibitory to Ca fluxes associated with sparks. RyR is known to be poorly selective to Ca, and a robust model of ion permeation through a single RyR (described by Gillespie) predicts a significant K+ counterflux under physiological conditions

effects of FKBP12 & FKBP12.6 on RyR determined, non-homologous residues assessed, FKBP12 mutant generated that acts like FKBP12.6

Determine nature/location of luminal Ca-sensor preserved on RyR/IP3R

ATP -> activates RyR through Ca-dependent & Ca-independent mechs. ADP partial agonist.

describe regulation of RyR by FKBPs

ATP --> activates RyR (maximal 2mM, bell shaped) w/\Ca, gating kinetics differ w\. ADP + ATP limits efficacy of ATP in activating.

cryo-EM was used to describe the channel in a closed state

described a closed state in which the four S6 segments constrict at the inner activation gate. ion conducting pathway formed by S6 segments & selectivity filter, spans ~90A. adjacent to selectivity filter = -vely charged residues thought to attract cations.

E4872Q mutation abolishes luminal Ca sensitivity in vitro & protects against SOICR in vivo.

RyR mediates its own countercurrent by mediating K+ influx to the SR