Page 62 - YORAM RUDY BOOK FINAL

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The CaMKKII Regulatory Pathway 16

The CaMKII regulatory pathway was first integrated into the HRd model of a canine
ventricular myocyte and later into the ORd model of the human ventricular cell . On activation
18
16
by Ca /calmodulin, CaMKII phosphorylates neighboring subunits (autophosphorylation), which
2+
enables detection of Ca -spike frequency . CaMKII substrates in cardiac myocytes include I ,
2+
153
CaL
RyR2, SR Ca -ATPase (SR Ca -uptake pump), and phospholamban (PLB) (see Figure 2.1).
2+
2+
Implementation of the CaMKII effects on these substrates is described in reference . Figure 2.41A
16
shows CaT during pacing over a wide range of frequencies. The top row are recorded traces and
the bottom row are corresponding simulated CaT, showing close agreement between simulation
and experiment. Diastolic Ca and amplitude of CaT increased as pacing frequency increased
2+
from 0.25 to 2.0 Hz (positive CaT-frequency relation, Figure 2.41B). This relationship involved

increase in CaMKII activity when pacing frequency was increased. Elevated CaMKII activity also
resulted in increased excitation-contraction (ECC) gain (Figure 2.41C) and PLB phosphorylation
(Figure 2.41D). CaMKII inhibition reversed the CaT-frequency relationship, producing a negative
CaT-frequency relation for frequencies > 1Hz (Figure 2.41B) and flattened the ECC gain-frequency
relation (Figure 2.41C). Mechanistically, CaMKII increased CaT at fast rates by increasing SR Ca
2+
uptake, which increased SR Ca load, by increasing peak I , which increased the trigger for SR Ca
2+
CaL
release, and by increasing RyR2 Ca release directly.
2+

CaMKII is hyperphosphorylated in the infarct boarder zone. Simulations of this condition
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in a mathematical model of the canine myocyte (the HRd model) showed the following effects :
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1. Increased Ca leak from the SR, causing abnormal Ca cycling and reduced CaT; 2. Flattening of
the APD rate-adaptation curve; 3. Altering sodium channel kinetics, thereby reducing AP
upstroke velocity. Increased Ca leak can be associated with delayed after depolarizations (DADs)

and arrhythmic triggered activity 14a,90 . Slow upstroke velocity could be associated with slow
conduction, conduction block and reentrant activity. Therefore, the simulation results suggest a
possible role for CaMKII hyperactivity in arrhythmias in the infarct boarder zone.

The ß-adrenergic Cascade 155

Local signaling domains and numerous interacting molecular pathways and substrates
contribute to the whole-cell response of myocytes during ß-adrenergic stimulation (ßARS). In

ventricular myocytes, ßARS activates the ßAR/G-protein/adenylyl cyclase (AC)/cyclic AMP (cAMP)/
protein kinase A (PKA) pathway that results in the phosphorylation of numerous intracellular
proteins (“substrates”), including I , I , PLB and the inhibitory troponin subunit (TnI). In addition,
CaL Ks
there are several feedback loops, such as ß-adrenergic receptor desensitization, that control the
temporal response of ßARS 156,157 . There is also interaction between the ß-adrenergic cascade and
the CaMKII regulatory pathway. Localized signaling in subcellular domains is essential for precise
specific regulation (“local control”); it allows multiple signaling pathways that affect the second