Abstract
Protein kinase-D (PKD) is increasingly recognized as a key regulatory signaling hub in cardiac glucose uptake and also a major player in the development of hypertrophy. Glucose is one of the predominant energy substrates for the heart to support contraction. However, a cardiac substrate switch toward glucose over-usage is associated with the development of cardiac hypertrophy. Hence, regulation of PKD activity must be strictly coordinated. This review provides mechanistic insights into the acute and chronic regulatory functions of PKD signaling in the healthy and hypertrophied heart. First an overview of the activation pathways of PKD1, the most abundant isoform in the heart, is provided. Then the various regulatory roles of the PKD isoforms in the heart in relation to cardiac glucose and fatty acid metabolism, contraction, morphology, function, and the development of cardiac hypertrophy are described. Finally, these findings are integrated and the possibility of targeting this kinase as a novel strategy to combat cardiac diseases is discussed.
Highlights
The heart has a high demand for energy substrates in order to sustain perpetual cycles of contraction and relaxation
GLUT1 is known as the constitutive glucose transporter that permanently resides at the sarcolemma
GLUT1 mainly contributes to basal glucose uptake and GLUT4 to glucose uptake induced by a variety of physiological and pharmacological stimuli [3, 6]
Summary
The heart has a high demand for energy substrates in order to sustain perpetual cycles of contraction and relaxation. The notion that PKD1 functions in the contraction-induced regulation of cardiac glucose uptake indicates that PKD1 signaling is involved in both acute and chronic adaptations of the heart to external stimuli. We will first provide an overview of the PKD family, mostly focused on PKD1 activation, we will discuss the various roles of the PKDs in the heart related to cardiac glucose and fatty acid metabolism, contraction, morphology and function.
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