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Address corresondence to Thomas Zimmer, Friedrich Schiller University, Jena Institute of Physiology II, Teichgraben 8, 07740 Jena, Germany. Fax: (49) 3641-933202; E-mail: tzim{at}mti-n.uni-jena.de
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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subunit of voltage-gated Na+ channels of brain, skeletal muscle, and cardiomyocytes is functionally modulated by the accessory ß1, but not the ß2 subunit. In the present study, we used ß1/ß2 chimeras to identify molecular regions within the ß1 subunit that are responsible for both the increase of the current density and the acceleration of recovery from inactivation of the human heart Na+ channel (hH1). The channels were expressed in Xenopus oocytes. As a control, we coexpressed the ß1/ß2 chimeras with rat brain IIA channels. In agreement with previous studies, the ß1 extracellular domain sufficed to modulate IIA channel function. In contrast to this, the extracellular domain of the ß1 subunit alone was ineffective to modulate hH1. Instead, the putative membrane anchor plus either the intracellular or the extracellular domain of the ß1 subunit was required. An exchange of the ß1 membrane anchor by the corresponding ß2 subunit region almost completely abolished the effects of the ß1 subunit on hH1, suggesting that the ß1 membrane anchor plays a crucial role for the modulation of the cardiac Na+ channel isoform. It is concluded that the ß1 subunit modulates the cardiac and the neuronal channel isoforms by different molecular interactions: hH1 channels via the membrane anchor plus additional intracellular or extracellular regions, and IIA channels via the extracellular region only.
Key Words: ß2 subunit • cardiac electrophysiology • Nav1.2 • Nav1.5 • subunit interaction
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). These channels are heteromultimeric proteins of the plasma membrane consisting of a pore-forming subunit and accessory ß subunits. Screening for cDNAs encoding Na+ channel subunits revealed the existence of 10 and 3 ß subunit isoforms in mammalian cells (Goldin, 2001).
As demonstrated by heterologous expression experiments, the subunit determines the main electrophysiological and pharmacological properties of a given Na+ channel complex (Catterall, 1992), while two of the three ß subunits (ß1 and ß3) modulate the function of the subunits (Patton et al., 1994; Morgan et al., 2000). When expressed in Xenopus oocytes, the ß1 subunit increases the current amplitude and accelerates the recovery from inactivation in currents generated by cardiac (Nuss et al., 1995; Qu et al., 1995), skeletal muscle (Wallner et al., 1993; Yang et al., 1993; Makita et al., 1994) and neuronal Na+ channels (Isom et al., 1992; Smith and Goldin, 1998; Vijayaragavan et al., 2001). In addition to this, neuronal and skeletal muscle Na+ channels require the ß1 subunit for fast inactivation (Isom et al., 1992; Wallner et al., 1993; Yang et al., 1993; Makita et al., 1994; Patton et al., 1994; Nuss et al., 1995; Smith and Goldin, 1998; Vijayaragavan et al., 2001).
The molecular mechanisms leading to the increased current densities and to the accelerated recovery from inactivation have not been elucidated. Recent data indicate that the human heart Na+ channel (hH1; Gellens et al., 1992) assembles with the ß1 subunit already within the endoplasmic reticulum (Zimmer et al., 2002). This may result in an improved trafficking of the channel complex to the plasma membrane, similarly as reported for ATP-sensitive K+ channels (Zerangue et al., 1999). Single-channel experiments with hH1 indicated that the larger current amplitude upon ß1 coexpression is not due to a change of the channel open probability (Nuss et al., 1995). Together, these data suggest that increased current amplitudes are due to an increase of the number of functional channels in the plasma membrane. In this context, it is interesting to note that Na+ channel ß subunits are highly homologous to cell adhesion molecules (CAM) of the Ig superfamiliy (Isom et al., 1995; Isom, 2001). Their extracellular domains bind to extracellular matrix molecules (Srinivasan et al., 1998; Xiao et al., 1999), strongly suggesting a function of Na+ channel ß subunits in promoting cell–cell contacts and in modulating localization and cell-surface density of subunits.
Molecular regions of the ß1 subunit that are responsible for the modulation of the electrophysiological properties of IIA and human skeletal muscle (hSKM1) Na+ channels are located within the extracellular domain (Chen and Cannon, 1995; McCormick et al., 1998, 1999). In these studies it was shown that neither the putative ß1 membrane anchor nor the ß1 intracellular domain is required for the ß1-like modulation of sodium channel gating. This result was further substantiated by the finding that the corresponding ß1 subunit response element in IIA and hSKM1 channels is localized within an extracellular loop (domain IV, loop S5/S6; Makita et al., 1996; Qu et al., 1999).
In the present study we used chimeras and deletion variants of ß1 and ß2 subunits to identify ß1 molecular regions involved in the modulation of hH1. We show that—in contrast to the result with IIA channels—the ß1 extracellular domain is neither sufficient nor necessary for the ß1 effect on the recovery kinetics and current density of hH1 channels expressed in Xenopus oocytes. Instead, the putative membrane anchor plus either the extracellular or the intracellular domain of the ß1 subunit are required to modulate hH1. We conclude that hH1 and IIA channels interact specifically with different molecular regions of the ß1 subunit.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), for the rat brain IIA Na+ channel (EMBL/GenBank/DDBJ accession no. X61149; Auld et al., 1988) and for the rat ß1 subunit (EMBL/GenBank/DDBJ accession no. M91808; Isom et al., 1992) were provided by A.L. George (Vanderbilt University), A.L. Goldin (University of California) and W. Stühmer (Max Planck Institute, Göttingen), respectively. The ß2 subunit (EMBL/GenBank/DDBJ accession no. U37026, Isom et al., 1995) was isolated by RT-PCR from the human brain astrocytoma cell line 1321N1, as already described (Zimmer et al., 2002).
Recombinant DNA Procedures
To obtain a comparable translation efficiency of the different ß subunit variants in Xenopus oocytes, we subcloned each of the ß subunit constructs into the same in vitro transcription vector (pGEMHEnew; Liman et al., 1992). This vector contains the T7 promoter, a 5'-untranslated region (UTR)* of the Xenopus ß-globin gene, a multicloning site (mcs) used to insert the ß subunit variants, and a 3'-UTR of the Xenopus ß-globin gene. Since this 3'-UTR is not present in the hH1-containing vector pSP64T-hH1, we linearized all ß subunit plasmids for in vitro transcription using a restriction site within the mcs downstream to the ß subunit sequence so that also the resulting cRNAs did not contain the ß-globin 3'-UTR. Thus, the hH1 and each of the ß subunit cRNAs were composed of the ß-globin 5'-UTR and the hH1 or the respective ß subunit sequences.
The ß1 cDNA was isolated from pSPNaß and subcloned into pGEMHEnew using the HindIII-XbaI and EcoRI-XbaI sites, respectively, resulting in pGEM-ß1. The HindIII and EcoRI sites were treated with Klenow enzyme to allow for blunt end ligation. The ß2 cDNA was inserted into the BamHI-HindIII site of pGEMHEnew, resulting in pGEM-ß2, as described previously (Zimmer et al., 2002).
The ß subunit chimeras constructed are shown in Fig. 2. To create the constructs ß122, ß211, ß122a, ß211a, and ß221, the desired ß1 and ß2 subunit regions were first separately amplified by PCR and then linked by a recombinant PCR step (Higuchi, 1989) using the following internal primer pairs: 5'-CACCCACAATCTCTGACACGATGGATGCCAT-3' and 5'-CGTGTCAGAGATTGTGGGTGCCTCCGTCGG-3' for the construction of ß122, 5'-GGTGGCCGTGATCATGATGTACGTGCTCAT-3' and 5'-ACATCATGATCACGGCCACCGTGAAGTCCC-3' for the construction of ß211, 5'-CCTGCAGATGGATCTTCTTGACGACGCTGG-3' and 5'-CAAGAAGATCCATCTGCAGGTCCTCATGGA-3' for the construction of ß122a, 5'-TGGCAAGATCCACCTGGAGGTGGTGGACAA-3' and 5'-CCTCCAGGTGGATCTTGCCATGGCCACGGT-3' for the construction of ß211a, and 5'-GGTGCTGATGGTGTACTGCTACAAGAAGAT-3' and 5'-AGCAGTACACCATCAGCACCAAGATGACCA-3' for the construction of ß221. Recombinant fragments were subcloned into the BamHI-HindIII (ß122, ß122a) or Asp718-EcoRI sites (ß211, ß211a, ß221) of pGEMHEnew, resulting in pGEM-ß122, pGEM-ß122a, and in pGEM-ß211, pGEM-ß211a, pGEM-ß221, respectively. Chimeras ß121 and ß212 were created using the ß122 and ß211 constructs as initial templates for PCR and the following internal primer pairs: 5'-GGTGCTGATGGTGTACTGCTACAAGAAGAT-3' and 5'-AGCAGTACACCATCAGCACCAAGATGACCA-3' for the construction of ß121, and 5'-ACTTGACCACCATCTCCGCCACGAGCCATA-3' and 5'-GGCGGAGATGGTGGTCAAGTGTGTGAGGAG-3' for the construction of ß212. Recombinant PCR fragments were subcloned into the Asp718-Bsp1407 (ß121) and Asp718-Bpu1102 sites (ß212) of pGEM-ß1 and pGEM-ß2, resulting in pGEM-ß121 and pGEM-ß212, respectively. The deletion variants ß11
and ß21 were constructed by PCR. For the introduction of a stop codon at the desired position (underlined in the primer sequence) and an XbaI site for the subsequent cloning step (indicated in italics in the primer sequence), we used oligonucleotide 5'-AAATCTAGACTAAATCTTCTTGTAGCAGTACAC-3' as one of the flanking primers. The sequence of the T7 promoter in pGEM-ß1 and pGEM-ß211 served as the second primer site. The ß11 and ß21 PCR fragments were subcloned into the Asp718-XbaI site of pGEMHEnew, resulting in pGEM-ß11 and pGEM-ß21, respectively. Construct ß12 was also obtained by PCR. We used oligonucleotide 5'-AAAAAGCTTCAACCTGCTCTACCTCCTCACACACTTGACCAC-3' (underlined: stop codon; italics: HindIII site) and the T7 promoter sequence to amplify the shortened chimera from plasmid pGEM-ß122. The product was subcloned into the Asp718-HindIII site of pGEMHEnew, resulting in pGEM-ß12.
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Heterologous Expression in Xenopus Oocytes
Capped cRNAs of hH1 and of IIA were prepared by SpeI and NotI digestion of plasmids pSP64T-hH1 and pNa200, respectively, followed by in vitro transcription reaction with SP6 (hH1) and T7 (IIA) RNA polymerase (Roche Diagnostics GmbH). Vectors pGEM-ß2, pGEM-ß122, pGEM-ß122a, pGEM-ß211, pGEM-ß211a, pGEM-ß221, pGEM-ß121, pGEM-ß212, and pGEM-ß21 were linearized by HindIII digestion, and vectors pGEM-ß1 and pGEM-ß11 were linearized by XbaI digestion. The in vitro transcription reaction was performed using T7 RNA polymerase.
Oocytes from Xenopus laevis were obtained as described previously (Zimmer et al., 2002). Glass micropipettes were used to inject a cRNA volume per oocyte of 40–60 nl. Concentrations of the different cRNA preparations were assessed by agarose gel electrophoresis using the 0.24–9.5 kb RNA ladder from GIBCO BRL. The hH1 and IIA cRNA preparations were injected at a final concentration of 
0.1 µg/µl and 0.05 µg/µl, respectively. The different cRNAs encoding the ß subunit variants were at a concentration of 0.2 µg/µl. Thus, the final molar ratio of hH1 to ß subunit variant was 1:20 at the cRNA level. Injected oocytes were incubated for 3 d at 18°C in Barth medium. In control experiments, we tested the influence of the hH1/ß1 cRNA ratio on current density and recovery from inactivation. Significant modulation of hH1 currents was already observed at a 1:1 ratio. The effects saturated at a ratio of 1:5 to 1:10, and were obtained also at higher ß1 cRNA concentrations (1:40). However, only about one fifth of the ß1 cRNA was required to modulate hH1 channels when incorporating the 3'-UTR of the ß-globin sequence into the ß1 cRNA (NotI digestion of pGEM-ß1). Current amplitudes did not increase when coinjecting undiluted ß1 cRNA containing this ß-globin sequence, although the recovery from inactivation of hH1 was clearly accelerated (unpublished data). A 3- to 10-fold dilution of this ß1 cRNA containing both the 5'- and 3'-UTR of the Xenopus ß-globin gene resulted in two- to fourfold higher peak current amplitudes accompanied by the described effect on the recovery kinetics. We think that this 3'-UTR enhances the translation efficiency of the ß1 subunit. Thus, expression of hH1 whose cRNA does not contain this sequence is probably suppressed relative to the expression of ß1.
Electrophysiology
Whole-cell Na+ currents were recorded with the two-microelectrode voltage clamp technique using a commercial amplifier (OC725C; Warner Instruments Corp.). Glass microelectrodes were filled with 3 M KCl solution. The microelectrode resistance was between 0.2 and 0.5 M
. The bath solution contained (in mM): 20 NaCl, 97.5 KCl, 1.8 CaCl2, 10 HEPES/KOH, pH 7.2. The currents were elicited by test potentials from -80 to 40 mV in 5-mV increments from a holding potential of -120 mV. The pulsing frequency was 0.2 Hz. Recovery from inactivation was determined with a standard protocol (Fig. 1 C, inset) at a frequency of 0.2 Hz. The amplitude of INa, measured 3 d after injection at the test potential of -25 mV (hH1) and -10 mV (IIA) was between 0.5 to 5.0 µA. The recovery from inactivation was determined from Na+ currents with an amplitude between 1.5 to 3 µA. Recording and analysis of the data were performed on a PC with the ISO2 software (MFK). The sampling rate was 20 kHz.
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RESULTS |
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The similarity of the ß1 subunit effects on current density and recovery from inactivation of the cardiac and brain Na+ channels suggests a similar mechanism for the /ß1 subunit interaction. We tested this hypothesis by coexpressing various ß1/ß2 subunit chimeras (Fig. 2) with hH1 and IIA channels in the oocyte system. Although both ß subunits share little contiguous primary sequence similarity (14% identity throughout the sequences), their conformation and topology are presumably very similar (Isom et al., 1992; Isom et al., 1995). Both subunits are predicted to be membrane anchored, exposing the larger NH2-terminal domain to the extracellular side and the smaller COOH-terminal region into the cytosol (Fig. 2).
hH1 and IIA Channels Are Modulated by Different ß1 Subunit Regions
Coexpression of chimera ß122 that consisted of the ß1 extracellular domain (ED), the ß2 membrane anchor (MA) and the ß2 intracellular domain (ID; see Figs. 2 and 3 A) did neither enhance the current density nor accelerate the recovery from inactivation of hH1 channels (Fig. 3, B and C). In contrast, ß1-like effects on hH1 currents were observed when coexpressing the opposite chimera ß211, indicating that the MA plus the ID of the ß1 subunit are required to modulate hH1 channels (Fig. 3, B and C, Table I). In control experiments, we tested the effect of both chimeras on IIA channels and observed that only ß122, but not ß211, modulated the inactivation time course, current density, and recovery from inactivation (Fig. 3, D–F). This indicates that the ß1 ED is necessary and sufficient to modulate IIA channels, similarly as reported previously (McCormick et al., 1999). Coexpression of ß211, however, that was sufficient to modulate hH1, had no effect on IIA channels (Fig. 3, B and C). The same results were obtained when using a structurally similar pair of ß subunit chimeras (ß122a and ß211a in Fig. 2; Table I). In conclusion, the cardiac Na+ channel isoform hH1 is modulated by the ß1 MA plus the ID, whereas the ß1 ED was sufficient to modulate the neuronal isoform IIA.
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, Fig. 5, Table I), confirming that the ß1 MA is not sufficient to modulate hH1 currents. In addition to this membrane-spanning region, the ß1 ID is required for an efficient modulation of hH1 channels (ß21 vs. ß211, Figs. 3 and 5, Table I).
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or ß12, respectively), and expressed these deletion variants lacking the ß1 ID with hH1 or IIA channels (Fig. 6 A).
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accelerated the recovery from inactivation of hH1 currents (Fig. 6, B and C, Table I). In contrast to this, coexpression of ß12 did not produce ß1-like effects on hH1. This result shows that the ß1 MA is required in ß11 to modulate hH1 channels. In ß11, a few amino acids are probably exposed to the intracellular side, thus belonging to the ID. These residues should, however, not be responsible for the modulation of hH1, because the same amino acids are present in ß21 which had no effect on hH1 (Fig. 5).
In case of IIA channels, both ß11 and ß12 accelerated the inactivation time course and the recovery process from inactivation (Fig. 6, D–F), again confirming that the ß1 ED suffices to modulate IIA channels.
Although the hH1 and IIA current amplitudes increased significantly when coexpressing ß11, respective values were clearly smaller compared with the data obtained with hH1/ß1 or IIA/ß1 channels (Fig. 6, B and E). Thus, the absence of the ß1 ID caused a partial loss of function, suggesting an /ß1 subunit interaction on the cytoplasmic side.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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/ß1 interaction is not mediated by a conserved molecular mechanism in IIA and hH1 channels. In contrast to the results obtained with the Na+ channel isoforms of brain (McCormick et al., 1998, 1999; this study) and skeletal muscle (Chen and Cannon, 1995), the extracellular domain of the ß1 subunit was neither sufficient nor required to modulate the cardiac-specific Na+ channel isoform. Instead, the ß1 membrane anchor was identified as a structural requirement for ß1-like modulation of hH1. All chimeras lacking this region failed to increase current density and to accelerate recovery from inactivation.
However, the ß1 membrane anchor alone did not modulate hH1 currents (see ß212 in Fig. 5). To accelerate the recovery process, additional molecular regions of the ß1 subunit were necessary: either the ID in ß211 or the ED in ß11. This surprising result suggests two alternative mechanisms for the acceleration of the recovery from inactivation: one mediated by extracellular and the other by intracellular hH1/ß1 interaction sites. Both mechanisms obviously require the primary interaction of the ß1 membrane–spanning region with a putative intramembrane site in hH1. This interaction could then facilitate an exposure of the ID and the ED of the ß1 subunit to respective interaction sites of hH1, finally resulting in a specific hH1/ß1 interaction and in the observed current modulation.
In addition to the effect on the recovery of hH1 channels, a strong increase in the current density was only observed with the wild-type ß1 subunit and with chimera ß211 (see Fig. 3). Deletion of the ß1 intracellular domain (ß11 and ß21) significantly reduced the peak current amplitude, suggesting an important role of the ß1 intracellular domain for an efficient hH1/ß1 subunit interaction. We speculate that the absence of this domain reduces the binding affinity between ß1 and hH1, finally resulting in a decreased cell surface expression of functional channels. Supporting this view, Meadows et al. (2001) recently showed by coimmunoprecipitation experiments that the deletion of 34 amino acids at the COOH terminus of the ß1 subunit drastically reduced the ß1 binding affinity to IIA channels in a mammalian cell line.
The intracellular ß1 domain may exert its effect on hH1 channels not only by a direct subunit interaction, but also through the interaction with other proteins. Recent studies provided evidence for cytoskeletal interactions of the ß1 subunit through ankyrin (Chauhan et al., 2000; Malhotra et al., 2000) and for the binding of the ß1, but not the ß2 subunit, to receptor tyrosine phosphatase ß (Ratcliffe et al., 2000). Thus, the hH1/ß1 interaction at the intracellular side might be regulated by cytoskeletal proteins or by a specific phosphorylation site in the ß1 intracellular domain.
Recently, an alternative spliced variant of the ß1 subunit has been reported (ß1A; Kazen-Gillespie et al., 2000), which is expressed in the heart. Similar to the ß2 subunit, this splice variant possesses a membrane-spanning and intracellular domain that shows no obvious sequence similarities with the respective regions of the ß1 subunit (protein sequence identity of 10.5% and 8.6% of the ß1A ID vs. the corresponding residues in ß1 and ß2, respectively). Therefore, it is likely that ß1A has either no or at least altered modulating effects on hH1. Respective coexpression studies with hH1/ß1A channels including ß1/ß1A chimeras could be a clue for the understanding of the physiological relevance of the alternative splicing of the ß1 subunit in the heart.
In conclusion, our data contribute to a better understanding of the hH1/ß1 interaction. We provide evidence that different molecular mechanisms underlie the ß1 modulatory effects in hH1/ß1 and IIA/ß1 channels. Future studies using site-directed mutagenesis and protein binding assays may reveal the corresponding key amino acids both in hH1 and in the ß1 subunit that determine the nature of the subunit interaction of the cardiac Na+ channel.
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FOOTNOTES |
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ACKNOWLEDGMENTS |
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This work was supported by grant Be1250/9-2 from the Deutsche Forschungsgemeinschaft to K. Benndorf and T. Zimmer, and by BMBF grant 01ZZ015/IZKF Jena to T. Zimmer.
Submitted: 23 August 2002
Revised: 17 October 2002
Accepted: 21 October 2002
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REFERENCES |
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subunit with novel gating properties. Neuron. 1:449–461.[CrossRef][Medline] subunit. J. Neurochem. 76:1871–1878.[CrossRef][Medline] subunits expressed in Xenopus oocytes. J. Gen. Physiol. 106:1171–1191. subunits. J. Biol. Chem. 269:17649–17655. subunit in voltage-dependent gating and modulation by ß1 subunits. J. Biol. Chem. 274:32647–32654.-subunit by the ß1-subunit. FEBS Lett. 336:535–539.[CrossRef][Medline] subunit isoform. Neuron. 11:915–922.[CrossRef][Medline]
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h values of hH1 versus hH1/ß1 channels were statistically indistinguishable (-30 mV: 
