Diversity of calcium signaling in cardiac calcium signaling: Changes in calcium signaling as a function of development and evolution

Abstract

Ca²⁺ is a universal signaling agent imperative to cardiac excitation contraction coupling. Here the development and modulation of the Ca²⁺ signaling pathways responsible for cardiac Ca²⁺ contraction are explored to determine whether changes in the Ca ²⁺ signaling pathways as a function of development and evolution are associated with the movement of the animal or species from slower to faster Ca²⁺ signaling.

Confocal Ca²⁺ imaging experiments were carried out on cultured and acutely isolated rat neonatal and juvenile cardiomyocytes to study the transitions in and functional expression of RyRs and IP₃Rs. Spontaneous Ca²⁺ oscillations in cultured neonatal cardiomycoytes had an adult excitation contraction coupling phenotype, with the requirement of membrane depolarization, trans-membrane Ca²⁺ flux, and CICR, but were capable of being driven by IP₃ activation to produce a slower oscillatory rate. Maturation from neonatal to juvenile involved an upregulation of both RyR and IP₃R-gated Ca²⁺ stores, but the IP₃R-gated Ca²⁺ signals were a smaller fraction of total Ca²⁺ signal in the juvenile versus neonatal myocytes. These data suggest an intermediate stage to Ca²⁺ signaling phenotypes between the embryo and adult where IP₃R Ca²⁺ signaling has a latent and inducible capacity to directly contribute to CICR and cardiac contraction but is being functionally replaced by the faster RyR Ca²⁺ signaling.

Molecular cloning, confocal Ca²⁺ imaging, and electrophysiology were performed to study the shark NCX. We demonstrated that the bimodal characteristics of the cloned shark's cAMP-mediated regulation resembled those found in freshly dissociated shark ventricular cardiomyocytes, persisted with different degrees of intracellular Ca²⁺-buffering, and were altered to unimodal inhibition after deletion-mutation of a unique shark insert. These results reveal that the unique bimodal regulatory characteristics of the shark NCX are rooted in its genetic code and are consistent with the idea that adaptive changes in ECC in different species involve the evolution of faster Ca ²⁺ signaling pathways.

Thus, the transition of Ca²⁺ signaling pathways from slow to faster ECC Ca²⁺ signaling is achieved in developing cardiomyocytes via transitions in the functional expression of the dominating Ca²⁺ signaling pathways and in different species via gene-based modifications of existing Ca²⁺ signaling pathways.