Enhanced activity and overexpression of Pannexin 1 (Panx1) channels contribute to neuronal pathologies such as epilepsy and Alzheimer’s disease (AD). The Panx1 channel ablation alters the hippocampus’s glutamatergic neurotransmission, synaptic plasticity, and memory flexibility. Nevertheless, Panx1-knockout (Panx1-KO) mice still retain the ability to learn, suggesting that compensatory mechanisms stabilize their neuronal activity. Here, we show that the absence of Panx1 in the adult brain promotes a series of structural and functional modifications in the Panx1-KO hippocampal synapses, preserving spontaneous activity. Compared to the wild-type (WT) condition, the adult hippocampal neurons of Panx1-KO mice exhibit enhanced excitability, a more complex dendritic branching, enhanced spine maturation, and an increased proportion of multiple synaptic contacts. These modifications seem to rely on the actin–cytoskeleton dynamics as an increase in the actin polymerization and an imbalance between the Rac1 and the RhoA GTPase activities were observed in Panx1-KO brain tissues. Our findings highlight a novel interaction between Panx1 channels, actin, and Rho GTPases, which appear to be relevant for synapse stability.

Hypobaric hypoxia under chromic conditions triggers hypoxic pulmonary vasoconstriction (HPV) and right ventricular hypertrophy (RVH). The role of zinc (Zn) under hypoxia is controversial and remains unclear. We evaluated the effect of Zn supplementation in prolonged hypobaric hypoxia on HIF2α/MTF-1/MT/ZIP12/PKCε pathway in the lung and RVH. Wistar rats were exposed to hypobaric hypoxia for 30 days and randomly allocated into three groups: chronic hypoxia (CH); intermittent hypoxia (2 days hypoxia/2 days normoxia; CIH); and normoxia (sea level control; NX). Each group was subdivided (n = 8) to receive either 1% Zn sulfate solution (z) or saline (s) intraperitoneally. Body weight, hemoglobin, and RVH were measured. Zn levels were evaluated in plasma and lung tissue. Additionally, the lipid peroxidation levels, HIF2α/MTF-1/MT/ZIP12/PKCε protein expression and pulmonary artery remodeling were measured in the lung. The CIH and CH groups showed decreased plasma Zn and body weight and increased hemoglobin, RVH, and vascular remodeling; the CH group also showed increased lipid peroxidation. Zn administration under hypobaric hypoxia upregulated the HIF2α/MTF-1/MT/ZIP12/PKCε pathway and increased RVH in the intermittent zinc group. Under intermittent hypobaric hypoxia, Zn dysregulation could participate in RVH development through alterations in the pulmonary HIF2α/MTF1/MT/ZIP12/PKCε pathway.

Chronic wounds are characterized by persistent inflammation and impaired fibroblast function, leading to defective tissue repair. Pannexin-1 (Panx1) channels regulate extracellular ATP release and purinergic signaling, processes implicated in inflammation and regeneration. Probenecid (PBN), a clinically approved Panx1 channels inhibitor, has emerged as a potential therapeutic modulator in chronic wounds; however, its compatibility with growth factor-mediated regenerative responses remains unclear. Here, we evaluated whether pharmacological inhibition of Panx1 channels alters βFGF-induced responses in human neonatal dermal fibroblasts (HDFn). Cells were treated with βFGF (10 ng/mL) in the presence or absence of PBN (200 μM), and migration, proliferation, extracellular matrix-related gene expression, extracellular ATP release, intracellular Ca²⁺ signaling, and Panx1 expression/localization were assessed. PBN did not significantly alter βFGF-induced migration, proliferation, or most extracellular matrix-related transcriptional responses, except for a further reduction in COL1A1 expression. In addition, βFGF did not modify PANX1 transcript levels, Panx1 protein abundance, or membrane localization. Although βFGF reduced extracellular ATP release and transiently modulated ATP-induced Ca²⁺ signaling, these effects occurred without detectable changes in Panx1 expression or localization. These findings support the compatibility of PBN with βFGF-driven regenerative responses in HDFn cells.