Purinergic signaling in embryonic and stem cell development

Abstract

Nucleotides are of crucial importance as carriers of energy in all organisms. However, the concept that in addition to their intracellular roles, nucleotides act as extracellular ligands specifically on receptors of the plasma membrane took longer to be accepted. Purinergic signaling exerted by purines and pyrimidines, principally ATP and adenosine, occurs throughout embryologic development in a wide variety of organisms, including amphibians, birds, and mammals. Cellular signaling, mediated by ATP, is present in development at very early stages, e.g., gastrulation of Xenopus and germ layer definition of chick embryo cells. Purinergic receptor expression and functions have been studied in the development of many organs, including the heart, eye, skeletal muscle and the nervous system. In vitro studies with stem cells revealed that purinergic receptors are involved in the processes of proliferation, differentiation, and phenotype determination of differentiated cells. Thus, nucleotides are able to induce various intracellular signaling pathways via crosstalk with other bioactive molecules acting on growth factor and neurotransmitter receptors. Since normal development is disturbed by dysfunction of purinergic signaling in animal models, further studies are needed to elucidate the functions of purinoceptor subtypes in developmental processes.

Cardiomyogenesis of embryonic stem cells upon purinergic receptor activation by ADP and ATP

“…Purinoceptors belong to those receptors which are widely expressed in early stages of ES cell differentiation and are involved in the regulation of several basic physiological processes including stem cell proliferation, differentiation, and recruitment [23,25].…”

“…All cardiogenic factors are integrated into transcriptional networks, among which [Ca 2+ ] i plays a principal role [16,17,22]. Purinergic receptors, also known as purinoceptors, belong to the first group of receptors which stimulate intracellular [Ca 2+ ] i signaling during the early time of embryonic development as well as cardiogenesis [23][24][25]. Extracellular nucleotides (purines and pyrimidines) activate different subtypes of purinergic receptors.…”

“…P2X receptors are ATP-activated ligand-gated cationic channels, unselectively permeable to Na + , K + , and Ca 2+ . The mammalian G-coupled metabotropic P2Y receptor family contains eight receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, P2Y14) based on phylogenic similarity [25,26]. P2Y receptors are stimulated by a range of purine and pyrimidine nucleotides (ATP, ADP, and to a lesser extend UTP, UDP, or UDP-glucose) [23,26,27].…”

“…The P2Y1 receptor is a major subtype expressed generally in all cell types, and it mainly involves in regulating cell proliferation and differentiation. Interestingly, the principal physiological agonist for P2Y1 is ADP rather than ATP [25,28].…”

“…[Ca 2+ ] i mobilization plays a central role in the regulation of gene transcription. For instance translocation of Mef2c, a cardiac-specific transcription factor, into the nucleus is a calcium-dependent process in the regulation of cardiac cell differentiation [22,25,27].…”