Blood oxygen regulation via P2Y12R expressed in the carotid body.

BACKGROUND: Peripheral blood oxygen monitoring via chemoreceptors in the carotid body (CB) is an integral function of the autonomic cardiorespiratory regulation. The presence of the purinergic P2Y12 receptor (P2Y12R) has been implicated in CB; however, the exact role of the receptor in O2 sensing and signal transduction is unknown. METHODS: The presence of P2Y12R was established by immunoblotting, RT qPCR and immunohistochemistry. Primary glomus cells were used to assess P2Y12R function during hypoxia and hypercapnia, where monoamines were measured by HPLC; calcium signal was recorded utilizing OGB-1 and N-STORM Super-Resolution System. Ingravescent hypoxia model was tested in anaesthetized mice of mixed gender and cardiorespiratory parameters were recorded in control and receptor-deficient or drug-treated experimental animals. RESULTS: Initially, the expression of P2Y12R in adult murine CB was confirmed. Hypoxia induced a P2Y12R-dependent release of monoamine transmitters from isolated CB cells. Receptor activation with the endogenous ligand ADP promoted release of neurotransmitters under normoxic conditions, while blockade disrupted the amplitude and duration of the intracellular calcium concentration. In anaesthetised mice, blockade of P2Y12R expressed in the CB abrogated the initiation of compensatory cardiorespiratory changes in hypoxic environment, while centrally inhibited receptors (i.e. microglial receptors) or receptor-deficiency induced by platelet depletion had limited influence on the physiological adjustment to hypoxia. CONCLUSIONS: Peripheral P2Y12R inhibition interfere with the complex mechanisms of acute oxygen sensing by influencing the calcium signalling and the release of neurotransmitter molecules to evoke compensatory response to hypoxia. Prospectively, the irreversible blockade of glomic receptors by anti-platelet drugs targeting P2Y12Rs, propose a potential, formerly unrecognized side-effect to anti-platelet medications in patients with pulmonary morbidities.

The antidepressant effect of short- and long-term zinc exposition is partly mediated by P2X7 receptors in male mice.

Background: As a member of the purinergic receptor family, divalent cation-regulated ionotropic P2X7 (P2rx7) plays a role in the pathophysiology of psychiatric disorders. This study aimed to investigate whether the effects of acute zinc administration and long-term zinc deprivation on depression-like behaviors in mice are mediated by P2X7 receptors. Methods: The antidepressant-like effect of elevated zinc level was studied using a single acute intraperitoneal injection in C57BL6/J wild-type and P2rx7 gene-deficient (P2rx7 -/-) young adult and elderly animals in the tail suspension test (TST) and the forced swim test (FST). In the long-term experiments, depression-like behavior caused by zinc deficiency was investigated with the continuous administration of zinc-reduced and control diets for 8 weeks, followed by the same behavioral tests. The actual change in zinc levels owing to the treatments was examined by assaying serum zinc levels. Changes in monoamine and brain-derived neurotrophic factor (BDNF) levels were measured from the hippocampus and prefrontal cortex brain areas by enzyme-linked immunosorbent assay and high-performance liquid chromatography, respectively. Results: A single acute zinc treatment increased the serum zinc level evoked antidepressant-like effect in both genotypes and age groups, except TST in elderly P2rx7 -/- animals, where no significant effect was detected. Likewise, the pro-depressant effect of zinc deprivation was observed in young adult mice in the FST and TST, which was alleviated in the case of the TST in the absence of functional P2X7 receptors. Among elderly mice, no pro-depressant effect was observed in P2rx7 -/- mice in either tests. Treatment and genotype changes in monoamine and BDNF levels were also detected in the hippocampi. Conclusion: Changes in zinc intake were associated with age-related changes in behavior in the TST and FST. The antidepressant-like effect of zinc is partially mediated by the P2X7 receptor.