Frequency-dependent Acceleration of Relaxation in the Heart Depends on CaMKII, but not Phospholamban

Determinants of frequency-dependent contraction and relaxation of mammalian myocardium

“…They showed that FDAR occurs abruptly when frequency is raised from 0.1 to 2 Hz and that under these conditions the effect is essentially complete within a few beats. In addition, they documented a small increase in PLB Thr 17 and RyR Ser 2814 phosphorylation, (PLB<5%, RyR approximately 8%), but the time-course was much slower and did not coincide with FDAR. Essentially, this study shows that although CAMKII can phosphorylate several targets within the myocyte as a result of the increased frequency, these effects occur secondary to the actual acceleration of relaxation, and are thus not primarily responsible for FDAR.…”

“…Thus, it is conceivably that phosphorylation of phospholamban that is known to aid in increasing the SR calcium load with β-adrenergic stimulation, plays a similar role in the regulation of calcium handling with changes in frequency [14,15]. However, some studies have refuted this hypothesis, and did not find a role for phospholamban phosphorylation in frequency dependent activation [16,17]. An increase in cardiac contractility in vivo is primarily dependent upon adrenergic stimulation and PLB phosphorylation, which suggests that PLB phosphorylation is the primary mechanism for increased Ca 2+ transport.…”

“…CaMKII is an attractive candidate to be mainly responsible for modulation of FDAR because it is activated by elevated calcium and can increase SERCA pump activity by phosphorylating PLB. Studies from Bassani et al [36] and De Santiago and coworkers [17] indicated that FDAR is dependent on CaMKII activation, and studies in isolated myocytes suggested that phosphorylation of the Thr 17 residue of PLN is responsible for FDAR [15]. However there are other studies that failed to show either an FDAR dependence on CaMKII activation [2,37,38] or a significant increase in PLB phosphorylation [16,37].…”

“…However there are other studies that failed to show either an FDAR dependence on CaMKII activation [2,37,38] or a significant increase in PLB phosphorylation [16,37]. The role of CaMKII in FDAR was investigated using isolated trabeculae and/or myocytes from PLB-KO mouse and rat hearts [17,39]. These studies relied on CaMKII inhibitors (1 μm KN-93 or 20 μm altocamtide-2 peptide AIP).…”

“…As a result of these factors, the calcium decline may critically and predominantly modulate relaxation in unloaded myocytes, and thus manipulation of calcium decline will directly affect relaxation kinetics when load is absent. Indeed, in the unloaded isolated myocyte at sub-physiological pacing frequencies, inhibition of CAMKII targeted to the SR blunts FDAR [17,40]. However, relaxation of the myocardium under loaded conditions as it occurs in vivo is likely governed in a significantly different manner.…”