CaMKII activation and regulation in adult cardiac myocytes

Project Summary/ Abstract
Ca-Calmodulin dependent protein kinase (CaMKII) is an important regulator of cardiac function,
and dysfunction in pathological states, regulating ion channels, Ca transporters, myofilaments
and nuclear transcription. CaMKII may normally fine-tune these processes. But in pathological
conditions like heart failure (HF), chronic autonomous CaMKII activation can over-phosphorylate
targets, contributing to arrhythmogenesis due to acute effects on several ion channels and Ca-
handling proteins. Chronic CaMKII activation is also a hallmark of several pathological states
and acute or genetic CaMKII inhibition can reduce arrhythmias and the progression of HF. Thus
understanding fundamental aspects of CaMKII regulation in cardiac myocytes is critical
understanding dysfunction and potential therapeutics. We and others discovered several novel
post-translational modifications (PTMs) that can trap CaMKII in an activated state, rather than
turning on & off rapidly with local Ca transients. Autophosphorylation, oxidation, GlcNAcylation
and S-nitrosylation within a regulatory hotspot on CaMKII creates memory and autonomous
activity, even when Ca/CaM falls. There are also 3 PTMs at other sites that suppress CaMKII
activation. Aims 1 and 2 will directly measure how these PTMs differentially affect activation and
memory of CaMKII in adult cardiac myocytes, to fill a major knowledge gap in this field. Aim 3
will test whether CaMKII S-nitrosylation at a single site is required for the heart’s intrinsic
response to increase Ca transients and contraction in response to acute and chronic pressure
overload (or the Anrep effect). CaMKII has well-recognized roles in HF with reduced ejection
(HFrEF), but its role in HF with preserved ejection (HFpEF) is unclear. Aim 4 will directly test the
engagement of CaMKII in two new HFpEF models. The proposed studies will have major impact
on our understanding of how CaMKII activity is regulated in heart, in ways that promote
pathology and might be targets for therapeutic intervention.

Grant Number: 5R01HL142282-08
NIH Institute/Center: NIH
Principal Investigator: Donald Bers