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Noncanonical Roles of Voltage-Gated Sodium Channels

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Noncanonical Roles of Voltage-Gated Sodium Channels Neuron Perspective Noncanonical Roles of Voltage-Gated Sodium Channels Joel A. Black1,2 and Stephen G. Waxman1,2,* 1Department of Neurology, Yale University School of Medicine, New Haven, CT 06520, USA 2Center for Neuroscience and Regeneration Research, Veterans Affairs Connecticut Healthcare System, West Haven, CT 06516, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.neuron.2013.09.012 The Hodgkin-Huxley formulation, at its 60th anniversary, remains a bastion of neuroscience. Sodium chan- nels Nav1.1–Nav1.3 and Nav1.6–Nav1.9 support electrogenesis in neurons and are often considered ‘‘neuronal,’’ whereas Nav1.4 and Nav1.5 drive electrogenesis in skeletal and cardiac muscle. These channels are, however, expressed in cell types that are not considered electrically excitable. Here, we discuss sodium channel expression in diverse nonexcitable cell types, including astrocytes, NG2 cells, microglia, macro- phages, and cancer cells, and review evidence of noncanonical roles, including regulation of effector func- tions such as phagocytosis, motility, Na+/K+-ATPase activity, and metastatic activity. Armed with powerful + 2+ techniques for monitoring channel activity and for real-time assessment of [Na ]i and [Ca ]i, neuroscientists are poised to expand the understanding of noncanonical roles of sodium channels in healthy and diseased tissues. In Brief able (termed here ‘‘nonexcitable cells’’). Moreover, there is abun- Sodium channels support electrogenesis in neurons and skeletal dant evidence demonstrating that sodium channels participate and cardiac muscle. They are, however, expressed in cell types in or regulate multiple effector functions in these nonexcitable that are not considered electrically excitable, including astro- cells. It is becoming clear, for example, that sodium chan- cytes, NG2 cells, microglia, macrophages, and cancer cells, nels—located not only on the plasma membrane delimiting the where they regulate phagocytosis, motility, Na+/K+-ATPase cell from the extracellular space but also, in some cases, on activity, and metastatic activity. intracellular membranes surrounding specific organelles within We have now passed the 60th anniversary of the Hodgkin and the cell—contribute to processes as diverse as phagocytosis, Huxley (1952) discovery of the role of sodium channels in electro- motility, the release of bioactive molecules, and the regulation genesis, and it remains a bastion of modern neuroscience: of Na+/K+-ATPase activity in nonneuronal cells, including cells voltage-gated sodium channels are major players in action- as disparate as microglia and astrocytes within the CNS, where potential electrogenesis. Seven of the voltage-gated sodium they participate in the response to CNS injury, and cancer cells, channels (Nav1.1–Nav1.3 and Nav1.6–Nav1.9) play major where they contribute to motility and invasiveness. The neurosci- roles in electrogenesis in neurons and are often considered ence community, which has a long history of discoveries on ‘‘neuronal,’’ whereas Nav1.4 is the muscle sodium channel and sodium channels and their function and which possesses an Nav1.5 is the predominant cardiac myocyte channel. The canon- armamentarium of powerful tools that can help explicate the ical role of sodium channels in impulse electrogenesis and con- function of sodium channels, is in a unique position to elucidate duction in these excitable cells has been well established and is the functions of sodium channels in nonexcitable cells, as well as relatively well understood (see Rush et al., 2007; Catterall, 2012). in neurons. In this article, we discuss the expression of sodium Indeed, major aspects of the pathophysiology of neurological channels in nonexcitable cells and review accumulating evi- disorders, including epilepsy (George, 2004; Helbig et al., dence showing that, within these cells, these channels play 2008; Reid et al., 2009; Eijkelkamp et al., 2012; Oliva et al., noncanonical roles and participate in multiple, diverse effector 2012), multiple sclerosis (MS) (Waxman, 2006), peripheral neu- functions. ropathy (Faber et al., 2012a,2012b), neuropathic pain (Wood, 2007; Dib-Hajj et al., 2010,2013), muscle diseases such as myo- Sodium Channels Are Expressed in Nonexcitable Cells tonic dystrophy (Jurkat-Rott et al., 2010; Stunnenberg et al., It is now known that nine different genes encode nine distinct 2010) and periodic paralysis (Cannon 2010), and cardiac disor- sodium channels (Nav1.1–Nav1.9), which are expressed with ders such as Brugada syndrome (Campuzano et al., 2010; diverse temporal and regional patterns in excitable cells (Catter- Song and Shou, 2012; Tarradas et al., 2013), can be attributed all et al., 2005) and are variably associated with b-subunits to abnormalities of electrical excitability due to sodium channel (Patino and Isom, 2010; Brackenbury and Isom, 2011). Although dysfunction. Nonetheless, beyond the expression of sodium all voltage-gated sodium channels share a common overall channels in neurons, myocytes, cardiomyocytes, and other structural motif and considerable homology, the different sub- excitable cells, there is convincing evidence that multiple sub- types display distinct voltage dependence and kinetic and phar- types of voltage-gated sodium channels—the same channels macological properties (Catterall et al., 2005), and the repertoire that support electrogenesis in nerve cells, muscle cells, and car- of sodium channel subtypes expressed in a particular type of diac myocytes—are expressed and play major functional roles in excitable cell significantly contributes to its pattern of electrores- cell types that have been traditionally considered to be nonexcit- ponsiveness (see, e.g., Waxman 2000; Rush et al., 2007). 280 Neuron 80, October 16, 2013 ª2013 Elsevier Inc. Neuron Perspective Table 1. Voltage-Gated Sodium Channels in Nonexcitable Cells Cell type Sodium Currents or Channels References Astrocytes TTX-S, TTX-R currents; Nav1.2, Bevan et al., 1985, 1987; Nowak et al., 1987; Barres et al., 1988; Sontheimer Nav1.3, Nav1.5, Nav1.6 et al., 1991, 1992, 1994; Sontheimer and Waxman, 1992; Thio and Sontheimer, 1993; Black et al., 1995a, 1998, 2010; Kressin et al., 1995; Bordey and Sontheimer, 1998; Reese and Caldwell, 1999 Cancer cells Nav1.4, Nav1.5, Nav1.6, Nav1.7 Fraser et al., 2003, 2005; Roger et al., 2003; Diss et al., 2004, 2005; Brackenbury and Djamgoz, 2006; Gillet et al., 2009; Yang et al., 2012 Chrondrocytes TTX-S Sugimoto et al., 1996 Dendritic cells Nav1.7 Zsiros et al., 2009; Kis-Toth et al., 2011 Endothelial cells TTX-S, TTX-R currents; Nav1.4, Gordienko and Tsukahara, 1994; Gosling et al., 1998;Walsh et al., 1998; Nav1.5, Nav1.6 Traub et al., 1999 Fibroblasts TTX-S, TTX-R; Nav1.2, Nav1.3, Munson et al., 1979; Estacion 1991; Li et al., 2009; Chatelier et al., 2012 Nav1.5, Nav1.6, Nav1.7 Keratinocytes Nav1.1, Nav1.6, Nav1.8 Zhao et al., 2008 Islet b-cells TTX-S; Nav1.2, Nav1.3 Donatsch et al., 1977; Pressel and Misler, 1991; Philipson et al., 1993; Barnett et al., 1995; Eberhardson and Grapengiesser, 1999 Macrophages TTX-S current; Nav1.5, Nav1.6 Schmidtmayer et al., 1994; Carrithers et al., 2007, 2009, 2011; Black et al., 2013 Microglia TTX-S current; Nav1.1, Nav1.5, Korotzer and Cotman, 1992; No¨ renberg et al., 1994; Craner et al., 2005; Black Nav1.6 et al., 2009; Nicholson and Randall, 2009 Mu¨ ller glia TTX-S, TTX-R currents; Nav1.6, Chao et al., 1994; Francke et al., 1996; O’Brien et al., 2008; Linnertz et al., 2011 Nav1.9 Odontoblasts Nav1.2 Allard et al., 2006 Oligodendrocyte precursor TTX-S current Bevan et al., 1987; Williamson et al., 1997; Chen et al., 2008; Ka´ rado´ ttir et al., cells (NG2+) 2008; Tong et al., 2009 Osteoblasts Nav1.2 Black et al., 1995b Red blood cells Nav1.4, Nav1.7 Hoffman et al., 2004 Schwann cells TTX-S current; Nav1.2, Nav1.3 Chiu et al., 1984; Howe and Ritchie, 1990; Oh et al., 1994 T lymphocytes TTX-S, TTX-R currents; Nav1.5 DeCoursey et al., 1985, 1987; Lai et al., 2000; Fraser et al., 2004; Lo et al., 2012 Nav1.1, Nav1.2, and Nav1.6 are expressed in both central and glial and immune cells to endothelial and cancer cells, had peripheral neurons, whereas Nav1.7–Nav1.9 are preferentially been shown to express voltage-gated sodium currents, and it expressed in peripheral neurons (Beckh et al., 1989; Felts has been shown that nonexcitable cells can express multiple et al., 1997; Gong et al., 1999; Schaller and Caldwell, 2003; Cat- sodium channel subtypes (Table 1). terall et al., 2005; Dib-Hajj et al., 2013). Nav1.3 is present in the Patch-clamp recordings have confirmed the expression of adult human brain (Chen et al., 2000; Whitaker et al., 2001; Thim- functional sodium channels in cell types as divergent as astro- mapaya et al., 2005), but it is predominantly expressed during cytes (Barres et al., 1988; Sontheimer et al., 1992; Sontheimer embryonic and early postnatal periods in rodents. Nav1.3 is and Waxman, 1992), oligodendrocyte precursor cells (Son- upregulated in dorsal root ganglion neurons in adult rodents after theimer et al., 1989; Kettenmann et al., 1991; Kressin et al., nerve injury (Waxman et al., 1994; Black et al., 1999) and contrib- 1995; Chen et al., 2008; Ka´ rado´ ttir et al., 2008), Schwann cells utes to hyperexcitability of these cells and thus neuropathic pain (Howe and Ritchie, 1990), fibroblasts (Estacion 1991; Li et al., (Cummins and Waxman, 1997; Samad et al., 2013). Nav1.4 is 2009), breast and prostate cancer cells (Fraser et al., predominantly expressed in skeletal muscle (Barchi et al., 2003,2005; Roger et al., 2003; Brackenbury and Djamgoz, 1984; Trimmer et al., 1989), whereas Nav1.5 is the principal 2006; Ding et al., 2008; Gillet et al., 2009), and macrophages sodium channel in cardiac muscle (Gellens et al., 1992; Clancy and microglia (Korotzer and Cotman, 1992; No¨ renberg et al., and Kass 2002; Fozzard 2002).
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