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Fig. 10.2 Schematics of
β
-adrenergic singling network, calcium handling, and electrophysiology
of a ventricular myocyte in a model developed by Saucerman et al. (
2003
)
cycling dynamics in cardiac myocytes. The Ca
2+
release channel proteins,
ryanodine receptors (RyRs), are clustered proximity to L-type Ca
2+
channel
clusters, forming CRUs. A unifying cardiac excitation-contraction coupling in
terms of a CRU is illustrated in Fig.
10.3b
(Bers
2002
). A ventricular myocyte
contains about 20,000 CRUs. CRUs are coupled via Ca
2+
diffusion in the cytosolic
and SR space, forming a three-dimensional (3D) CRU network inside a cell.
A T-tubular system (Fig.
10.3c
) facilitates effective communication of the 3D
network with the extracellular space, resulting in synchronous Ca
2+
release and
thus synchronous contraction of the cell. Intracellular Ca
2+
cycling dynamics
emerging from the CRU network are responsible for the formation of Ca
2+
clocks
for sino-atrial nodal cells (Lakatta et al.
2010
; Maltsev et al.
2011
) as well as Ca
2+
waves causing ventricular arrhythmias (Rovetti et al.
2010
; Nivala et al.
2012b
;
ter Keurs and Boyden
2007
).
Ca
2+
release in a CRU exhibits a discrete and random behavior, called Ca
2+
sparks
(Cheng and Lederer
2008
; Cheng et al.
1993
). Many experimental studies
(Cheng et al.
1996
;Wiereta .
1997
; Marchant and Parker
2001
; Bootman
et al.
1997
) have demonstrated a Ca
2+
signaling hierarchy, showing a transition
from Ca
2+
sparks to Ca
2+
waves and whole-cell Ca
2+
oscillations. A question is:
How does the transition from sparks to waves and oscillations occur? Using a CRU
network model we developed recently (Nivala et al.
2012a
), we were able to recapit-
ulate this Ca
2+
signaling hierarchy (Fig.
10.4a
). The amount of Ca
2+
released from the
SR due to random opening of one or two RyRs is small, which results in a quark
(labeled as “q” in Fig.
10.4a
). When several RyRs happen to randomly open at the
same moment, the amount of Ca
2+
released is large enough to initiate Ca
2+
-induced
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