Calcium (Ca) is the key regulator of cardiac contraction during excitation-contraction
(E-C) coupling. However, differences exist between the amount of
Ca being transported into the myocytes upon electrical stimulation
as compared to Ca released from the sarcoplasmic reticulum (SR).
Moreover, alterations in E-C coupling occur in cardiac hypertrophy
and heart failure. In addition to the direct effects of Ca on the
myofilaments, Ca plays a pivotal role in activation of a number of
Ca-dependent proteins or second messengers, which can modulate E-C
coupling. Of these proteins, calmodulin (CaM) and Ca-CaM-dependent
kinase II (CaMKII) are of special interest in the heart because of
their role of modulating Ca influx, SR Ca release, and SR Ca uptake
during E-C coupling. Indeed, CaM and CaMKII may be associated with
some ion channels and Ca transporters and both can modulate acute
cellular Ca handling. In addition to the changes in Ca, CaM and CaMKII
signals from beat-to-beat, changes may occur on a longer time scale.
These may occur over seconds to minutes involving phosphorylation/dephosphorylation
reactions, and even a longer time frame in altering gene transcription
(excitation-transcription (E-T) coupling) in hypertrophic signaling
and heart failure. Here we review the classical role of Ca in E-C
coupling and extend this view to the role of the Ca-dependent proteins
CaM and CaMKII in modulating E-C coupling and their contribution
to E-T coupling.