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Pannexin1: A mediator of NMDA and adrenergic receptor signaling

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Sci. Signal.  08 Mar 2016:
Vol. 9, Issue 418, pp. ec49
DOI: 10.1126/scisignal.aaf6061

Pannexin1 (Panx1) forms a nonselective channel in cell plasma membranes. NMDA receptors are a type of ionotropic glutamate receptor. Weilinger et al. found a “metabotropic” signaling pathway for NMDA receptors that is involved in excitotoxicity. Ligand binding to both the glutamate site and the modulatory site occupied by glycine or serine triggered excitotoxic signaling in hippocampal neurons through a mechanism that did not involve the channel function of NMDA receptors. Instead, these NDMA receptors formed a heterotrimeric complex with Panx1 and the tyrosine kinase Src, which activated Panx1. Panx1 mediated the cytotoxic current in these neurons. Importantly, a peptide derived from the C-terminal region of Panx1, which contained a site phosphorylated in an NMDA-dependent manner and interfered with this pathway, limited neuronal death and improved sensorimotor function in rodents subjected to experimentally induced stroke. Thus, disrupting this metabotropic NMDA receptor–activated Panx1-Src pathway may be a therapeutic strategy for treating stroke without causing the undesired side effects associated with other NMDA receptor–targeted therapies. NDMA receptors are not the only receptors coupled to Panx1 channels. Billaud et al. found a connection between Panx1 and α1 adrenergic receptors (α1ARs), which are Gq-coupled G protein–coupled receptors (GPCRs), in smooth muscle cells. In this case, peptides from a region in the first intracellular loop of Panx1 disrupted vasoconstriction mediated by activation of α1ARs. The tyrosine residue in this region of Panx1 was required for α1AR-mediated vasoconstriction in mice, suggesting that phosphorylation may be involved in this regulatory pathway as well. These studies highlight “noncanonical” signaling pathways downstream of an ionotropic receptor (NMDA receptors) and a Gq-coupled GPCR (α1ARs).

N. L. Weilinger, A. W. Lohman, B. D Rakai, E. M. Ma, J. Bialecki, V. Maslieieva, T. Rilea, M. V. Bandet, N. T. Ikuta, L. Scott, M. A. Colicos, G. C. Teskey, I. R. Winship, R. J. Thompson, Metabotropic NMDA receptor signaling couples Src family kinases to pannexin-1 during excitotoxicity. Nat. Neurosci. 19, 432–442 (2016). [PubMed]

M. Billaud, Y.-H. Chiu, A. W. Lohman, T. Parpaite, J. T. Butcher, S. M. Mutchler, L. J. DeLalio, M. V. Artamonov, J. K. Sandilos, A. K. Best, A. V. Somlyo, R. J. Thompson, T. H. Le, K. S. Ravichandran, D. A. Bayliss, B. E. Isakson, A molecular signature in the pannexin1 intracellular loop confers channel activation by the α1 adrenoreceptor in smooth muscle cells. Sci. Signal. 8, ra17 (2015). [Abstract]