肌质网钙释放通道的调节质钙释放通道的调节
余志斌
航空航天生理学教研室
(RYR, Ryanodine receptor)
1.Excitation-Contraction Coupling
2.DHPR-RYR coupling in structure 2DHPR-RYR coupling in structure
3.Mechanical coupling and CICR
4.DHPR
5.RYR
6.Regulation of RYR
6Regulation of RYR
7.RYR and diseases
8.Agonists and antagonists of RYR
1Excitation Contraction Coupling 1.Excitation-Contraction Coupling
Action potential
Action potential
T-tubules
DHPRs
Ca2+Mechanical
RYRs
Ca2+release
Upstream
TnC
Myosin-actin interaction Downstream
Myosin actin interaction Myofilament sliding
Contraction
2.DHPR-RYR coupling in structure p g
A:Triads
B:peripheral p p
couplings
C:Dyads
y
Feet structure Feet structure
DHPR三维结构及其与RYR的关系
Cardiac DHPR-RYR coupling
DHPR-RYR coupling in skeletal muscle
3.Mechanical coupling and CICR
p g
Cardiac muscle Cardiac muscle
Skeletal muscle Skeletal muscle
4.DHPR
α1 176 kDa
α2 147 kDa
147kDa
β 56 kDa
γ 34kDa
δ1 28 kDa
δ2 24 kDa
24kDa
Isoforms:
α1c α1s
L L-型钙离子通道选择性阻滞剂
1a类(二氢吡啶类)：Nifedipine 1b类(硫氮卓类)：Diltiazem
1c类(苯烷胺类)：Verapamil
三类L-型钙离子通道选择性阻滞剂作用位点的示意图
5.RYR
565 kDa
Tetrad
RYR1 5037aa
RYR2 4976aa
RYR3 4872aa
N-terminal domain 0-600aa Central domain 2100-2500aa Channel domain 41005000aa Channel domain4100-5000aa
6.Regulation of RYR
6R l ti f RYR
?Ion
?Small molecule
?Protein-protein interaction
?Phosphorylation
it l ti/l t thi l ti ?S-nitrosylation/S-glutathionylation
Oxidation to disulfides
?Oxidation to disulfides
调节：通道的稳定性，释放量，激活与失活速率
Ion regulation
Binding
site Ion regulation Ca 2+
Binding site A-site 4032aa I site 615/18731903aa Mg 2+/H +I-site 615/1873-1903 aa
Small molecules
Small molecules
ATP an activator of RYR1 ATP ti t f RYR1 Pi ibl i hibit
Pi a possible inhibitor
Protein-protein interaction
p
Cytosol proteins Binding sites
p
DHPR Ⅱ-Ⅲloop 450-1500aa Junctophilin1,2(JP1,2)
FKBP12/12.6(Calstabin1/2) 305-1937/2416-2430/3799-4967aa
()
CaM(Calmodulin) 3581-3610/1982-1999(Apo-CaM) Sorcin ?
Homer 1773-1783
SR luminal proteins
Junctin
T i di
Triadin
Calsequestrin(CSQ)
HRC/Sarcalumenin/Calreticulin