Type I and type II Na+ channel ?-subunit polypeptides exhibit distinct spatial and temporal patterning, and association with auxiliary subunits in rat brain

Abstract

Here we investigate differences in the temporal and spatial patterning, and subunit interactions of two of the major Na+ channel α‐subunit isoforms in mammalian brain, the type I and type II Na+ channels. By using subtype‐specific antibodies, we find that both isoforms are abundant in adult rat brain, where both interact with the covalently bound β2 auxiliary subunit. Immunoblot analysis reveals complementary levels of type I and type II in different brain regions, with the highest levels of type I in brainstem, cortex, substantia nigra, and caudate, where it is found predominantly on the soma of neurons, and the highest levels of type II in globus pallidus, hippocampus and thalamus, where it is preferentially localized to axons. Developmentally, type I Na+ channel polypeptide expression in brain increases dramatically during the third postnatal week, peaks at the end of the first postnatal month, and then decreases such that adult levels are ≈ 50% of those at peak. Type II Na+ channel polypeptide expression in brain also undergoes large increases in the third postnatal week, but levels continue to increase such that peak expression levels are maintained in adult animals. Type I Na+ channels are found associated with the auxiliary β2 subunit at all ages, whereas free type II Na+ channels exist during the first two postnatal weeks. Thus, although expression of these two Na+ channel α subunits in heterologous systems yields currents with very similar electrophysiological and pharmacological properties, their distinct spatial and temporal patterning, and association with auxiliary subunits in brain, suggest that they perform distinct, nonoverlapping functions in situ. J. Comp. Neurol. 412:342–352, 1999. © 1999 Wiley‐Liss, Inc.

Reduced Sodium Current in Purkinje Neurons from NaV1.1 Mutant Mice: Implications for Ataxia in Severe Myoclonic Epilepsy in Infancy

“…1A3). These results indicate that Na V 1.1 and Na V 1.6 are the predominant sodium channels in the cell bodies and dendrites of Purkinje neurons, in agreement with previous work (Westenbroek et al, 1989;Gong et al, 1999;Caldwell et al, 2000;Jenkins and Bennett, 2001;Schaller and Caldwell, 2003). The observed distribution of Na V channels in P13-P14 cerebellar neurons in our experiments indicates that Na V 1.1 and Na V 1.6 channels conduct nearly all sodium current in Purkinje neurons in this age range.…”

“…Anti-Na V 1.1 antibodies showed strong immunolabeling of the cell bodies of Purkinje neurons of WT mice ( Fig. 1 A1), similar to previous studies (Westenbroek et al, 1989;Gong et al, 1999). Labeling of the initial segment of the axons of Purkinje neurons with anti-Na V 1.1 antibodies is also visible in these images projecting below the cell body and continuing until the axons leave the plane of focus (Fig.…”

“…1 A1). In a similar study published after submission of this paper (Ogiwara et al, 2007), stronger staining of axons and less intense staining of cell bodies was observed for Purkinje neurons, in contrast to our work and previous studies (Westenbroek et al, 1989;Gong et al, 1999). Antibodies directed to different epitopes were used in these studies, so it is conceivable that the different relative intensity of staining of cell bodies versus axons may relate to different accessibility of these epitopes in cell bodies versus axons.…”

“…Na V 1.1, Na V 1.2, and Na V 1.6 channels are abundant in adult brain (Catterall, 2000;Goldin et al, 2000;Goldin, 2001;Trimmer and Rhodes, 2004). Na V 1.1 channels are primarily localized in cell bodies (Westenbroek et al, 1989(Westenbroek et al, , 1992, Na V 1.2 channels in unmyelinated axons and dendrites (Westenbroek et al, 1989(Westenbroek et al, , 1992Gong et al, 1999), and Na V 1.6 channels in myelinated axons and in dendrites Krzemien et al, 2000;Jenkins and Bennett, 2001). These channels participate in generation of both somatodendritic and axonal action potentials (Stuart and Sakmann, 1994;Johnston et al, 1996;Callaway and Ross, 1997;Raman and Bean, 1999b;Khaliq and Raman, 2006).…”

Familial Hemiplegic Migraine

“…They are a relatively minor component of total brain Na V channels, but are broadly expressed in many types of neurons, including hippocampal and cortical pyramidal cells and inhibitory interneurons, where they appear specifically localized in the soma and proximal dendrites. 88,89 The specific somatodendritic localization implies that Na V 1.1 channels may play a key role in mediating dendritic excitability, an important component of synaptic signal processing. 90 Deletion of the Na V 1.1␣ 1 gene had no discernible effect on Na ϩ currents in hippocampal pyramidal neurons of scna1a Ϫ/Ϫ mice, but led to 50% reduction of Na ϩ currents in inhibitory interneurons of heterozygote scna1a Ϫ/ϩ mice, suggesting that Na V 1.1 channels may be responsible for most or all of the Naϩ current in these interneurons, and for a minor fraction of the Na ϩ current in pyramidal cells.…”