Bicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury

Abstract

Homoeostatic regulation of the acid–base balance is essential for cellular functional integrity. However, little is known about the molecular mechanism through which the acid–base balance regulates cellular responses. Here, we report that bicarbonate ions activate a G protein-coupled receptor (GPCR), i.e., GPR30, which leads to Gq-coupled calcium responses. Gpr30-Venus knock-in mice reveal predominant expression of GPR30 in brain mural cells. Primary culture and fresh isolation of brain mural cells demonstrate bicarbonate-induced, GPR30-dependent calcium responses. GPR30-deficient male mice are protected against ischemia-reperfusion injury by a rapid blood flow recovery. Collectively, we identify a bicarbonate-sensing GPCR in brain mural cells that regulates blood flow and ischemia–reperfusion injury. Our results provide a perspective on the modulation of GPR30 signalling in the development of innovative therapies for ischaemic stroke. Moreover, our findings provide perspectives on acid/base sensing GPCRs, concomitantly modulating cellular responses depending on fluctuating ion concentrations under the acid–base homoeostasis.

Sodium Bicarbonate Decreases Alcohol Consumption in Mice

“…pH is an important biological factor in the body, as H + binds to proteins and alters the structure and function of bound proteins [8][9][10][11]. In the nervous system, pH affects the activities of many proteins, such as receptors, ion channels, transporters, and signaling proteins, thus resulting in physiological and pathological consequences [12][13][14]. A small amount of H + or HCO − 3 moving across cell membranes can cause a large pH change at the synapses, where the synaptic cleft is typically closed off; as a result, synaptic activity and the complex firing pattern can be altered.…”