Possible contribution of erythrocytes to the purinergic regulation of tissue oxygen delivery

Abstract

ATP release occurs in virtually all cell types and tissues. It is considered to be a key component of a ubiquitous, evolutionary ancient cell-to-cell communication system. The regulated release of ATP is also believed to be a part of a mechanism which facilitates matching tissue oxygen supply with demand. In this paper, ATP signaling is reviewed, regulation of tissue oxygen supply is outlined, and a concept attributing a role in this process to erythrocytes releasing ATP is discussed. Oxygen saturation of hemoglobin in erythrocytes traveling through a tissue reflects the level of oxygen utilization of that tissue. Therefore, erythrocytes can serve as local oxygen sensors. In the proposed mechanism, upon hemoglobin deoxygenation, Gi protein in the erythrocyte plasma membrane is activated. The activation of Gi protein initiates a cAMP-dependent pathway, leading to ATP efflux through pannexin channels. Extracellular ATP triggers vasodilatation via P2Y receptors on the surface of vascular endothelial cells, increasing blood flow in tissue regions of elevated oxygen consumption. Despite the abundance of compelling evidence in support of this concept, some details remain elusive, in particular, the process of Gi protein activation in response to hemoglobin desaturation. Furthermore, the involvement of cAMP, as well as the final conduit of ATP release from erythrocytes, remains controversial. Finally, the actual physiological relevance of the proposed regulatory mechanism will require further in vivo research.