1.A.25.2.1
Pannexin-1 (PANX1) has been reported to form functional, single membrane, cell surface channels (Penuela et al., 2007). Pannexin1 is part of the pore forming unit of the P2X(7) receptor death complex (Locovei et al., 2007). It can catalyze ATP release from cells (Huang and Roper, 2010) and promote ATP signalling in mice (Suadicani et al. 2012). It also promotes acetaminophen liver toxicity by allowing it to enter the cell (Maes et al. 2016).  Pannexin1 and pannexin2 channels show quaternary similarities to connexons but different oligomerization numbers (Ambrosi et al., 2010). Pannexin 1 constitutes the large conductance cation channel of cardiac myocytes (Kienitz et al., 2011). Pannexin 1 (Px1, Panx1) and pannexin 2 (Px2, Panx2) underlie channel function in neurons and contribute to ischemic brain damage (Bargiotas et al., 2011). Single cysteines in the extracellular and transmembrane regions modulate pannexin 1 channel function (Bunse et al., 2011).  Spreading depression triggers migraine headaches by activating neuronal pannexin1 (panx1) channels  (Karatas et al. 2013).  The channel in the mouse orthologue opens upon apoptosis (Spagnol et al. 2014). Transports ATP out of the cell since L-carbenoxolone (a Panx1 channel blocker) inhibits ATP release from the nasal mucosa, but flufenamic acid (a connexin channel blocker) and gadolinium (a stretch-activated channel blocker) do not (Ohbuchi et al. 2014). CALHM1 (TC#1.N.1.1.1) and PANX1 both play roles in ATP release and downstream ciliary beat frequency modulation following a mechanical stimulus in airway epithelial cells (Workman et al. 2017). Pannexin1 may play a role in the pathogenesis of liver disease (Willebrords et al. 2018). Inhibition of pannexin1 channel opening may provide a novel approach for the treatment of drug (acetaminophen-induced)-induced hepatotoxicity (Maes et al. 2017). Pannexin-1 is necessary for capillary tube formation on Matrigel and for VEGF-C-induced invasion. It is highly expressed in HDLECs and is required for in vitro lymphangiogenesis (Boucher et al. 2018). cryo-EM structure of a pannexin 1 reveals unique motifs for ion selection and inhibition. The cryo-EM structure of a pannexin 1 revealed unique motifs for ion selection and inhibition (Michalski et al. 2020). In another study, Deng et al. 2020 obtained near-atomic-resolution structures of human and frog PANX1 determined by cryo-EM that revealed a heptameric channel architecture. Compatible with ATP permeation, the transmembrane pore and cytoplasmic vestibule were exceptionally wide. An extracellular tryptophan ring located at the outer pore created a constriction site, potentially functioning as a molecular sieve that restricts the sizes of permeable substrates. Pannexin 1 channels in renin-expressing cells influence renin secretion and homeostasis (DeLalio et al. 2020). Structures of human pannexin 1 have revealed ion pathways and mechanism of gating (Ruan et al. 2020). PANX1 is critical for functions such as blood pressure regulation, apoptotic cell clearance and human oocyte development. Ruan et al. 2020 presented several structures of human PANX1 in a heptameric assembly at resolutions of up to 2.8 Å, including an apo state, a caspase-7-cleaved state and a carbenoxolone-bound state. A gating mechanism was revealed that involves two ion-conducting pathways. Under normal cellular conditions, the intracellular entry of the wide main pore is physically plugged by the C-terminal tail. Small anions are conducted through narrow tunnels in the intracellular domain. These tunnels connect to the main pore and are gated by a long linker between the N-terminal helix and the first transmembrane helix. During apoptosis, the C-terminal tail is cleaved by caspase, allowing the release of ATP through the main pore. A carbenoxolone (a channel blocker)-binding site is embraced by W74 in the extracellular entrance. A gap-junction-like structure was observed as expected (Yen and Saier 2007; Chou et al. 2017). Navis et al. 2020 provided a review of the literature on Panx1 structural biology and known pharmacological agents that target it. The R217H mutation perturbs the conformational flexibility of the C-terminus, leading to channel dysfunction (Purohit and Bera 2021). Panx1 plays decisive roles in multiple physiological and pathological settings, including oxygen delivery to tissues, mucociliary clearance in airways, sepsis, neuropathic pain, and epilepsy. It exerts some of these roles in the context of purinergic signaling by providing a transmembrane pathway for ATP, but Panx1 can also act as a highly selective membrane channel for chloride ions without ATP permeability (Mim et al. 2021). Pannexin 1 regulates skeletal muscle regeneration by promoting bleb-based myoblast migration and fusion through a lipid based signaling mechanism (Suarez-Berumen et al. 2021).  Pannexin-1 activation by phosphorylation is crucial for platelet aggregation and thrombus formation (Metz and Elvers 2022). Data suggest that in response to hypotonic stress, the intact rat lens is capable of releasing ATP. This seems to be mediated via the opening of pannexin channels in a specific zone of the outer cortex of the lens (Suzuki-Kerr et al. 2022). Expression of pannexin1 in lung cancer brain metastasis and immune microenvironment has been reported (Abdo et al. 2023). Pannexin-1 (Panx1) hemichannels are non-selective transmembrane channels that play roles in intercellular signaling by allowing the permeation of ions and metabolites, such as ATP. Evidence suggests that Panx1 hemichannels control excitatory synaptic transmission. García-Rojas et al. 2023 studied the contribution of Panx1 to the GABAergic synaptic efficacy onto CA1 pyramidal neurons (PyNs) by using patch-clamp recordings and pharmacological approaches in wild-type and Panx1 knock-out (Panx1-KO) mice. Blockage of the Panx1 hemichannel with the mimetic peptide increased the synaptic level of endocannabinoids (eCB) and the activation of cannabinoid receptors type 1 (CB1Rs), which resulted in a decrease in hippocampal GABAergic efficacy, shifting excitation/inhibition (E/I) balance toward excitation and facilitating the induction of long-term potentiation. Thus, Panx1 strongly influences neuronal excitability and plays a key role in shaping synaptic changes affecting the amplitude and direction of plasticity as well as learning and memory processes (García-Rojas et al. 2023). Genetic deletion of PANX1 mitigates kidney tubular cell death, oxidative stress and mitochondrial damage after renal ischemia/reperfusion (I/R) injury through enhanced mitophagy. Mechanistically, PANX1 disrupts mitophagy by influencing the ATP-P2Y-mTOR signal pathway. Thus, PANX1 could be a biomarker for acute kidney injury (AKI) and a therapeutic target to alleviate AKI caused by I/R injury (Su et al. 2023). Blocking pannexin 1 channels alleviates peripheral inflammatory pain but not paclitaxel-induced neuropathy (Lemes et al. 2024).  Cx43 hemichannels and panx1 channels contribute to ethanol-induced astrocyte dysfunction and damage (Gómez et al. 2024).  Pannexin1 mediates early-life seizure-induced social behavior deficits (Obot et al. 2024). The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity (Santavanond et al. 2024).  A heterozygous missense variant of PANX1 causes human oocyte death and female infertility (Zhou et al. 2024).