Creatine kinase in non-muscle tissues and cells

Abstract

Over the past years, a concept for creatine kinase function, the 'PCr-circuit' model, has evolved. Based on this concept, multiple functions for the CK/PCr-system have been proposed, such as an energy buffering function, regulatory functions, as well as an energy transport function, mostly based on studies with muscle. While the temporal energy buffering and metabolic regulatory roles of CK are widely accepted, the spatial buffering or energy transport function, that is, the shuttling of PCr and Cr between sites of energy utilization and energy demand, is still being debated. There is, however, much circumstantial evidence, that supports the latter role of CK including the distinct, isoenzyme-specific subcellular localization of CK isoenzymes, the isolation and characterization of functionally coupled in vitro microcompartments of CK with a variety of cellular ATPases, and the observed functional coupling of mitochondrial oxidative phosphorylation with mitochondrial CK. New insight concerning the functions of the CK/PCr-system has been gained from recent M-CK null-mutant transgenic mice and by the investigation of CK localization and function in certain highly specialized non-muscle tissues and cells, such as electrocytes, retina photoreceptor cells, brain cells, kidney, salt glands, myometrium, placenta, pancreas, thymus, thyroid, intestinal brush-border epithelial cells, endothelial cells, cartilage and bone cells, macrophages, blood platelets, tumor and cancer cells. Studies with electric organ, including in vivo 31P-NMR, clearly reveal the buffer function of the CK/PCr-system in electrocytes and additionally corroborate a direct functional coupling of membrane-bound CK to the Na+/K(+)-ATPase. On the other hand, experiments with live sperm and recent in vivo 31P-NMR measurements on brain provide convincing evidence for the transport function of the CK/PCr-system. We report on new findings concerning the isoenzyme-specific cellular localization and subcellular compartmentation of CK isoenzymes in photoreceptor cells, in glial and neuronal cells of the cerebellum and in spermatozoa. Finally, the regulation of CK expression by hormones is discussed, and new developments concerning a connection of CK with malignancy and cancer are illuminated. Most interesting in this respect is the observed upregulation of CK expression by adenoviral oncogenes.

Creatine kinase, an ATP-generating enzyme, is required for thrombin receptor signaling to the cytoskeleton

“…The PAR-1-CKB interaction identified in these studies may also be important during other RhoA pathway-dependent thrombin signals that regulate cell viability, vascular endothelial permeability, platelet aggregation, and fibroblast stress fiber formation (8,18,43,52). CKB is also expressed in endothelium, platelets, and fibroblasts where PAR-1 mediates morphological responses (53,54). Preliminary studies in our laboratory suggest a similar CKB signaling mechanism may persist in these cells (unpublished observations).…”

“…Also, creatine kinase inhibitors reduce tumor cell motility (42), and the creatine kinase homolog arginine kinase is selectively concentrated in motile versus static neuronal growth cones (26). Why certain cellular reactions are preferentially coupled to ATP generated specifically by creatine kinase as opposed to other ATP generating systems remains enigmatic, although metabolite channeling within multienzyme complexes and the energetic advantage of the close apposition of creatine kinase to ATPases demonstrated in previous studies is an attractive explanation (23,38,54,56). An explicit function for creatine kinase during signal transduction is suggested by the recently demonstrated interaction with AMP-activated protein kinase and regulation of its kinase activity (57).…”

Thyroid Hormone-dependent Gene Expression Program for Xenopus Neural Development

“…Creatine kinases catalyze the transfer of phosphoryl groups from phosphocreatine to ATP (37). The brain-type CK is a major enzyme involved with energy metabolism in nonmuscle cells (45).…”

Inhibition of the Mitochondrial Permeability Transition by Creatine Kinase Substrates

“…Cr produced during this reaction is shuttled back to the mitochondria for recharging it to PCr. This energy shuttling system is particularly efficient in tissues with a very high and fluctuating energy demand like skeletal and cardiac muscle, as well as in brain and neural tissues (7). Thus, in addition to the generally accepted temporal energy buffering function, PCr also provides a means to spatially buffer energy reserves (3).…”