Calmodulin binding proteins provide domains of local Ca2+ signaling in cardiac myocytes

Abstract

Calmodulin (CaM) acts as a common Ca(2+) sensor for many signaling pathways, transducing local Ca(2+) signals into specific cellular outcomes. Many of CaM's signaling functions can be explained by its unique biochemical properties, including high and low affinity Ca(2+)-binding sites with slow and fast kinetics, respectively. CaM is expected to have a limited spatial range of action, emphasizing its role in local Ca(2+) signaling. Interactions with target proteins further fine-tune CaM signal transduction. Here, we focus on only three specific cellular targets for CaM signaling in cardiac myocytes: the L-type Ca(2+) channel, the ryanodine receptor, and the IP(3) receptor. We elaborate a working hypothesis that each channel is regulated by two distinct functional populations of CaM: dedicated CaM and promiscuous CaM. Dedicated CaM is typically tethered to each channel and directly regulates channel activity. In addition, a local pool of promiscuous CaM appears poised to sense local Ca(2+) signals and trigger downstream pathways such as Ca(2+)/CaM dependent-protein kinase II and calcineurin. Understanding how promiscuous CaM coordinates multiple distinct signaling pathways remains a challenge, but is aided by the use of mathematical modeling and a new generation of fluorescent biosensors. This article is part of a special issue entitled "Local Signaling in Myocytes."

Figure 1

Regulation of cardiac ion channels by dedicated and promiscuous calmodulin (CaM). Abbreviations: CaN, calcineurin; CaMKII, CaM-dependent protein kinase II; LTCC, L-type Ca²⁺ channel; Na_v1.5, voltage-dependent Na⁺ channel; RyR, ryanodine receptor; IP₃R, IP₃ receptor.

Figure 2

Computational model predictions of CaMKII and CaN activities in A) dyadic cleft and B) cytosol of a ventricular myocyte. Adapted from [9].