Cardiomyocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 258

5.10.3.2 Ryanodine Receptors

Three types of ryanodine receptors, i.e., ryanodine-sensitive Ca 2 + -release channels,
exist, 2 being cardiac isoforms [ 458 ]. They are arranged on the sarcoplasmic
reticular membrane in arrays at junctions between the sarcoplasmic reticulum and
sarcolemma on cell surface and in T tubules beneath Ca V 1.2 channels [ 459 ]. These
coupled channels exhibit simultaneous gating due to FKBP1a [ 460 ]. 89
Clusters of ryanodine receptors (30-260 channels acccording to mammal
species) in regions of close apposition between the sarcoplasmic reticulum
and sarcolemma forms functional couplons [ 461 ]. Couplon distribution (mean
transverse and longitudinal spacing m, respectively) explains the

difference in Ca 2 + diffusion during Ca 2 + sparks in axial and transverse directions.
Ryanodine receptor clusters exist around T tubules and sarcomeres, in particular
around myofilament edges (spacing of 0

∼ 0.8 and ∼ 1.8

. 78 ± 0 . 07 m in humans). Each bundle of

myofibrils is supplied by approximately 6 clusters.
Ryanodine channels RyR2 form junctional proteic complexes that include:
(1) calmodulin, which exerts Ca 2 + -dependent modulation of channel function;
(2) peptidyl prolyl cis-trans isomerase FKBP1b, or calstabin-2, (3) protein kinase-
A; (4) protein phosphatases PP1 and PP2; (5) calcium-binding modulator of calcium
release sorcin; as well as (6) other proteins at the luminal surface of the sarcoplasmic
reticulum, triadin, junctin, and calsequestrin, that participate in Ca 2 + buffering and
modulation of Ca 2 + release. The cardiac ryanodine receptor complex RyR2 consists
of 4 monomers and also phosphodiesterase-4D, among various other components.
In normal hearts, the opening of RyR2 channels is regulated by FKBP1b and
PDE4d. Loss of PDE4d from RyR2 is associated with increased local cAMP
levels. Therefore, activity of protein kinase-A rises, hence phosphorylating RyR2
monomers with loss of FKBP1b from the complex. Consequently, calcium leaks,
thereby leading to heart failure and arrhythmia [ 462 ].
Overexpression of the transcription factor early growth response EGR1 impedes
calsequestrin synthesis, but does not influence that of calreticulin, triadin, SERCA2a
pump, and phospholamban [ 463 ]. Moreover, calcium release from its cellular store
via calsequestrin-dependent ryanodine channels decreases, whereas calcium influx
from calreticulin-dependent inositol trisphosphate channels remains unaffected.
Transcription factor EGR1 binds to the CSQ2 gene promoter to control excitation-
contraction coupling at the level of the sarcoplasmic reticulum.

5.10.3.3 IP 3 Receptors

Inositol (1,4,5)-trisphosphate receptors release Ca 2 + from the sarcoplasmic retic-
ulum. Type-1 and -2 IP 3 Rs (IP 3 R1 and IP 3 R2) lodge predominantly in atria.

89 FK506-binding protein FKBP1a, or FKBP12, was originally identified as the cytosolic receptor
for the immunosuppressors FK506 (a.k.a. tacrolimus and fujimycin) and rapamycin.