Database search has led to the identification of a family of proteins, the pannexins, which share some structural features with the gap junction forming proteins of invertebrates and vertebrates. The function of these proteins has remained unclear so far. To test the possibility that pannexins underlie electrical communication in the brain, we have investigated their tissue distribution and functional properties. Here, we show that two of these genes, pannexin 1 (Px1) and Px2, are abundantly expressed in the CNS. In many neuronal cell populations, including hippocampus, olfactory bulb, cortex and cerebellum, there is coexpression of both pannexins, whereas in other brain regions, e.g., white matter, only Px1-positive cells were found. On expression in Xenopus oocytes, Px1, but not Px2 forms functional hemichannels. Coinjection of both pannexin RNAs results in hemichannels with functional properties that are different from those formed by Px1 only. In paired oocytes, Px1, alone and in combination with Px2, induces the formation of intercellular channels. The functional characteristics of homomeric Px1 versus heteromeric Px1͞Px2 channels and the different expression patterns of Px1 and Px2 in the brain indicate that pannexins form cell type-specific gap junctions with distinct properties that may subserve different functions.
Several new findings have emphasized the role of neuronspecific gap junction proteins (connexins) and electrical synapses in processing sensory information and in synchronizing the activity of neuronal networks. We have recently shown that pannexins constitute an additional family of proteins that can form gap junction channels in a heterologous expression system and are also widely expressed in distinct neuronal populations in the brain, where they may represent a novel class of electrical synapses. In this study, we have exploited the hemichannel-forming properties of pannexins to investigate their sensitivity to wellknown connexin blockers. By combining biochemical and electrophysiological approaches, we report here further evidence for the interaction of pannexin1 (Px1) with Px2 and demonstrate that the pharmacological sensitivity of heteromeric Px1/Px2 is similar to that of homomeric Px1 channels. In contrast to most connexins, both Px1 and Px1/Px2 hemichannels were not gated by external Ca 2+. In addition, they exhibited a remarkable sensitivity to blockade by carbenoxolone (with an IC 50 of $5 lM), whereas flufenamic acid exerted only a modest inhibitory effect. The opposite was true in the case of connexin46 (Cx46), thus indicating that gap junction blockers are able to selectively modulate pannexin and connexin channels. Intercellular channels are specialized structures that have emerged as a general feature of multicellular organisms to provide a direct pathway for the movement of ions and water-soluble molecules, usually less than 1000 Da, between adjacent cells (Bruzzone et al. 1996;Harris 2001;Saez et al. 2003). In their standard configuration, these channels have been shown to cluster in discrete regions of the plasma membrane called gap junctions, which are present in most organs in vertebrates, where they play a role during development and in the differentiated tissue (Lo 1996;Saez et al. 2003;Segretain and Falk 2004). Neuron-specific gap junctions, which represent the structural correlate of electrical synapses, establish developmentally regulated compartments of communicating cells that persist in the adult organism (Bennett and Goodenough 1978;Dermietzel et al. 1989;Peinado et al. 1993). Moreover, several new findings have emphasized their role in processing sensory information and in synchronizing the activity of neuronal networks (LeBeau et al. 2003;Bennett and Zukin 2004;Connors and Long 2004;Hormuzdi et al. 2004).Although it had been always assumed that in vertebrates these channels were formed only by members of the connexin family (Willecke et al. 2002), we have recently shown that another small group of proteins, the pannexins, display the ability to form intercellular channels in a heterologous Abbreviations used: bGA, b-glycyrrhetinic acid; BSA, bovine serum albumin; CBX, carbenoxolone; Cx, connexin with the molecular mass in kDa as specified; DMEM, Dulbeco's modified Eagle's medium; DMSO, dimethylsulfoxide; EGFP, enhanced green fluorescent protein; FCS, fetal calf serum; FFA,...
IMPORTANCE Progressive supranuclear palsy (PSP) is a 4-repeat tauopathy. Region-specific tau aggregates establish the neuropathologic diagnosis of definite PSP post mortem. Future interventional trials against tau in PSP would strongly benefit from biomarkers that support diagnosis.OBJECTIVE To investigate the potential of the novel tau radiotracer 18 F-PI-2620 as a biomarker in patients with clinically diagnosed PSP. DESIGN, SETTING, AND PARTICIPANTSIn this cross-sectional study, participants underwent dynamic 18 F-PI-2620 positron emission tomography (PET) from 0 to 60 minutes after injection at 5 different centers (3 in Germany, 1 in the US, and 1 in Australia). Patients with PSP (including those with Richardson syndrome [RS]) according to Movement Disorder Society PSP criteria were examined together with healthy controls and controls with disease. Four additionally referred individuals with PSP-RS and 2 with PSP-non-RS were excluded from final data analysis owing to incomplete dynamic PET scans.
Direct cell-to-cell communication through specialized intercellular channels is a characteristic feature of virtually all multi-cellular organisms. The remarkable functional conservation of cell-to-cell coupling throughout the animal kingdom, however, is not matched at the molecular level of the structural protein components. Thus protostomes (including nematodes and flies) and deuterostomes (including all vertebrates) utilize two unrelated families of gap-junction genes, innexins and connexins, respectively. The recent discovery that pannexins, a novel group of proteins expressed by several organisms, are able to form intercellular channels has started a quest to understand their evolutionary relationship and functional contribution to cell communication in vivo. There are three pannexin genes in mammals, two of which are co-expressed in the developing and adult brain. Of note, pannexin1 can also form Ca2+-activated hemichannels that open at physiological extracellular Ca2+ concentrations and exhibit distinct pharmacological properties.
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