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1 Department of Physiology and Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, 95 N 2000 E, Salt Lake City, UT 84112, USA2 Medizinische Klinik und Poliklinik I, Klinikum der Universität München, Grosshadern, Marchioninistrasse 15, 81377 Munich, Germany3 Aventis Pharma Deutschland GmbH, D-65926 Frankfurt am Main, Germany
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Abstract |
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(Received 17 April 2004;
accepted after revision 20 April 2004;
first published online 23 April 2004)
Corresponding author N. Decher: Department of Physiology, University of Utah, 95 N 2000 E, Salt Lake City, UT 84112, USA. Email: niels.decher{at}gmx.net
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Introduction |
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KChIP proteins were first described as neuronal calcium sensors that bind to the N-terminus of Kv4 channels and modulate the surface expression and the rate of onset of IA inactivation (An et al. 2000). KChIP proteins also induce fast recovery from inactivation, a characteristic feature of native A-type K+ currents (An et al. 2000). Two KChIP2 isoforms were subsequently cloned from human heart, a 252 aa isoform (KChIP2b) lacking exon 3 and a 220 aa isoform (KChIP2c) lacking exons 2 and 3 (Bahring et al. 2001; Decher et al. 2001). Both isoforms altered the kinetics of Kv4.3 current in a manner that more closely resembled the native Ito,f current in epicardial tissues compared to Kv4.3 alone (Bahring et al. 2001; Decher et al. 2001). Ohya et al. (2001) reported that KChIP2a was present in the human heart. KChIP2c is the predominat isoform expressed in the human heart (Decher et al. 2001; Ohya et al. 2001) and the shift in the voltage dependence of inactivation by this isoform is more pronounced compared to KChIP2b (Decher et al. 2001). In humans and dogs the Ito,f gradient is paralleled by a KChIP2 mRNA-gradient, whereas in rodents the Ito,f gradient is paralleled by a Kv4 mRNA-gradient (Rosati et al. 2001). Subsequently, two additional KChIP2 isoforms, KChIP2t and KChIP2d, were described. KChIP2t (Deschenes et al. 2002) is identical to KChIP2c except for a short seven amino acid insert between exons 4 and 5. KChIP2d (Patel et al. 2002b) is the shortest of all the KChIPs and contains only the last three C-terminal exons. Surprisingly, this minimal KChIP2 isoform retains function, accelerating the recovery from inactivation and slowing the rate of inactivation of Kv4 currents (Patel et al. 2002b).
In this study we report three novel KChIP2 isoforms with alternative sequences in either the C-terminus (KChIP2e, KChIP2f) or the N-terminus (KChIP2g). These novel KChIP2 isoforms affect Kv4 properties differently from the previously described KChIP isoforms, extend the potential diversity of native transient outward potassium currents and provide new insights into KChIP domains involved in Kv4 channel regulation.
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Methods |
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The three KChIP2 isoforms cloned in this study were amplified from a cDNA that was obtained with primers annealing to the KChIP2 gene (5'-AAT TCC TAC AGG AGG GGC ACT C-3' and 5'-GAA AGA ACT GGG AGT AAA TCT GCT TG-3'). PCR of human heart cDNA was used to amplify a KChIP2 isoform previously registered in the NCBI database as KChIP2.5 (AF367019). In this study, this isoform is called KChIP2f, in accordance with the most frequently used nomenclature for KChIP2 proteins (Table 1, Fig. 1A). Similar to KChIP2c (AF347114), KChIP2f lacks exons 2 and 3 of KChIP2a. However, in addition KChIP2f is missing exon 7 and has an alternative exon 10, such that the last 15 amino acids of the C-terminus differ from the sequence of KChIP2c. The regular exon 10 of KChIP2f is replaced by the alternative exon 10 at a non-canonical splicing site, as the alternative exon 10 is adjacent to exon 9 on genomic DNA. PCR amplification of this isoform generated two PCR products: KChIP2f and a novel isoform (KChIP2e) that retained exon 7.
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Amplified products were automatically sequenced on both strands (ABI 310, Perkin Elmer) and cloned into pSGEM vector (Villmann et al. 1997). For expression studies in Xenopus laevis oocytes, cDNA was linearized and capped cRNA was synthesized using CapScribe Buffer (Roche) and T7 polymerase (Roche).
PCR on cDNA from human heart and brain
Expression of the novel KChIP2 isoforms was analysed using PCR on cDNA from human heart tissue that was obtained from explanted hearts of patients with dilated cardiomyopathy (DCM). Stratascript (Stratagene) was used for reverse transcription reactions. Studies were performed according to the Declaration of Helsinki. Informed consent was obtained before organs were explanted and the procedure was approved by the Ethical Review Board of the University of Munich. In addition, commercial cDNA from human brain (Clontech) was analysed.
KChIP2e and KChIP2f were detected with primers binding to exon 1 and the alternative exon 10: 5'-CCG CAA GGA GAG TTT GTC CG-3' and 5'-GGG TAA TGT AGA GGG CAG GGA GC-3'. KChIP2g was amplified with primers binding to the alternative exon 1 and regular exon 10: 5'-CAG CGC GAT CCC TCT ACC AGC-3' and 5'-GGA GGC GTA GGA TGA GGA TAG ACC-3'. The C-termini of KChIP2 with regular exon 10 were amplified by primers binding to exon 6 and the 3' UTR of the KChIP2 gene: 5'-CCT ATG CCA CTT TTC TCT TCA ATG C-3' and 5'-GGA GGC GTA GGA TGA GGA TAG ACC-3'. The C-termini of KChIP2e and of KChIP2f were amplified with primers binding to exon 6 and alternative exon 10: 5'-CCT ATG CCA CTT TTC TCT TCA ATG C-3' and 5'-GGG TAA TGT AGA GGG CAG GGA GC-3'. The annealing temperature for all primer combinations was 55°C. PCR products were verified by sequencing after subcloning into the pCRII TOPO vector (Clontech) using ABI-Sequencer 3700 (Kit Version 1.1).
Injection and voltage clamp of oocytes
Stage IV and V Xenopus laevis oocytes were isolated and injected with cRNA encoding Kv4.3 and/or KChIP2 isoforms using standard techniques (Goldin, 1991; Goldin & Sumikawa, 1992). Oocytes were isolated by dissection from adult Xenopus laevis. The frogs were anaesthetized by immersion in 0.2% tricaine for 15–20 min then placed on ice during dissection and removal of ovarian lobes. The incision was sutured closed and the frogs allowed to recover for about 1 month before removal of a second set of oocytes. Frogs were killed by pithing after anaesthetization with tricaine. RNA quality was judged by gel electrophoresis and its concentration quantified by UV spectroscopy using Ribogreen® (Molecular Probes, Eugene, OR, USA). Injected oocytes were cultured in Barth's solution supplemented with 50 µg ml–1 gentamycin and 1 mM pyruvate at 18°C for 1–3 days before use. Barth's solution contained (mM): 88 NaCl, 1 KCl, 0.4 CaCl2, 0.33 Ca(NO3)2, 1 MgSO4, 2.4 NaHCO3, 10 Hepes (pH 7.4).
For voltage-clamp experiments, oocytes were bathed in a modified ND96 solution containing (mM): 96 NaCl, 4 KCl, 1 MgC12, 1 CaC12, 5 Hepes (pH 7.6). Currents were recorded at room temperature (21–23°C) using standard two-microelectrode voltage-clamp techniques (Stuehmer, 1992) and a Geneclamp 500 amplifier, Digidata 1322a and pCLAMP 8 software (all from Axon Instruments, Union City, CA, USA).
The long isoform of human Kv4.3 (GenBank accession number NM_004980), the principal isoform in the heart (Dilks et al. 1999), was expressed alone or together with a single KChIP2 isoform. The voltage dependence of Kv4.3 channel inactivation was determined with a standard dual pulse protocol. From a holding potential of –80 mV, a 1.5 s conditioning pre-pulse to a variable voltage ranging from –100 to +10 mV was applied in 10 mV increments, followed by a 500 ms pulse to a test potential of +40 mV. Peak Kv4.3 currents recorded during the test pulse were normalized to the peak current measured following the most negative conditioning pre-pulse for each oocyte and the resulting relationship fitted with a Boltzmann function to estimate the half-point (V1/2) and the slope factor (k) for the voltage dependence of channel inactivation. Recovery from inactivation was analysed by a different dual pulse protocol. From a holding potential of –90 mV, channels were activated and inactivated by a 200 ms depolarization to +40 mV, then allowed to recover for a variable time at –90 mV before a test pulse to +40 mV was reapplied. The time constant for recovery from inactivation was obtained by a mono-exponential fit of the peak current amplitudes measured during the test pulse as a function of the recovery time at –90 mV.
Chemiluminescence assay
To monitor the surface expression of channels, a haemagglutinin (HA) protein epitope was inserted between Ala-291 and Phe-292 located within the S3–S4 extracellular loop of Kv4.3 short (Acc. no. AF205856). The amino acid sequence of the HA-tagged region was 291YPYDVPDYA292. The chemiluminescence assay was performed as described (Zerangue et al. 1999). Briefly, oocytes were blocked with ND96/1% IgG-free bovine serum albumin, labelled with anti-HA antibody and horseradish peroxidase-conjugated secondary antibody sequentially, then washed with ND96 solution. Oocytes were immersed in 100 µl of SuperSignal enzyme-linked immunosorbent assay substrate (Pierce Biotechnology Inc., Rockford, IL, USA). Relative light units (RLU) were counted with a Spectra Max Gemini EM microtiter plate luminometer (Molecular Devices, Sunnyvale, CA, USA).
Data analysis
Clampfit 8 (Axon Instruments) and Origin 7 (OriginLab Corp ., Northampton, MA, USA) software were used for data analyses. All curve fitting procedures were based on the simplex algorithm. Data are reported as the mean ±S.E.M. (n= number of oocytes). Statistical differences of averaged data were evaluated by Student's unpaired t test. Significance was assumed if P < 0.05.
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Results |
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Expression of the three novel KChIP2 isoforms was analysed by PCR on cDNA from human heart and brain. The C-terminal isoforms KChIP2e and KChIP2f are expressed in the heart, whereas KChIP2g is predominantly found in the brain (Fig. 2). Expression of KChIP2e and KChIP2f is restricted to the atrium, as no transcripts were detected in ventricles or in the brain (Fig. 2A). KChIP2g is predominantly expressed in the brain and barely detectable in the atria or ventricles (Fig. 2B). PCR amplification of the C-termini of KChIP2 isoforms with alternative exon 10 or regular exon 10 was in accordance with these findings, and it also appears that KChIP2e expression in the atria is much greater than KChIP2f (Fig. 2C and D). The C-termini of KChIP2 isoforms were amplified from exon 6 to the 3' UTR after exon 10 (Fig. 2C) or from exon 6 to alternative exon 10 (Fig. 2D). Transcripts were detected for C-termini with regular (Fig. 2C) or alternative (Fig. 2D) exon 10, either containing exon 7 (upper arrow) or lacking this exon (lower arrow). PCR products of the C-termini with alternative exon 10, representing the isoforms KChIP2e and KChIP2f, were present in atria but not the brain (Fig. 2A and D).
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KChIP2e and KChIP2f alter properties of Kv4.3 currents
We first describe the effects of the two KChIP2 isoforms (e and f) that were cloned from human heart cDNA. Expression of Kv4.3 cRNA in Xenopus oocytes induced a fast activating and inactivating A-type K+ current (Fig. 3A). Expression of KChIP2 isoforms alone did not generate currents in Xenopus oocytes (data not shown). Coinjection of Kv4.3 with an equal amount of KChIP2c or KChIP2f cRNA (15 ng each) significantly increased peak current amplitudes (Fig. 3B and D), whereas coinjection with KChIP2e decreased current (Fig. 3C). The relative changes in Kv4.3 current at +40 mV induced by coexpression of the KChIP isoforms is plotted in Fig. 3E. Current amplitudes were increased by factors of 2.28 ± 0.23 for KChIP2c (n= 10) and 1.42 ± 0.12 (n= 8) for KChIP2f. In contrast, coexpression with KChIP2e decreased relative current amplitude to 0.42 ± 0.12 (n= 8).
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KChIP2c alters the properties of Kv4.3 channel inactivation (Bahring et al. 2001; Decher et al. 2001). We compared the effects of KChIP2 isoforms c, e and f on the voltage dependence and kinetics of Kv4.3 inactivation when the two cRNAs were expressed at a 1 : 1 ratio (15 ng each). The time constants for the onset of inactivation (
) were determined for currents activated by depolarizing pulses to potentials ranging from +10 to +50 mV (Fig. 4A). Since the fast component of inactivation dominates Kv4 inactivation, time constants were determined from the first 200 ms of inactivating currents. For Kv4.3 alone was 69 ± 3 ms (n= 35) at +40 mV. Coexpression with KChIP2c and KChIP2f increased to 138 ± 9 ms (n= 10) and 91 ± 8 ms (n= 26), respectively. In contrast, KChIP2e decreased to 54 ± 2 ms (n= 18), an effect opposite to all previously described KChIP proteins. The effect of the KChIP2 isoforms c, e and f on the recovery from inactivation (recov) of Kv4.3 channels at –90 mV are shown in Fig. 4B. For Kv4.3 alone, recov was 220 ± 13 ms (n= 30). KChIP2c accelerated the recovery from inactivation as previously described (Bahring et al. 2001; Decher et al. 2001). KChIP2e slowed and KChIP2f had no effect on recov (Fig. 4B). Finally, we compared the voltage dependence of inactivation for Kv4.3 alone and in the presence of the KChIP2 isoforms c, e and f (Fig. 4C). For Kv4.3 alone the V1/2 of the relationship was –49.8 ± 0.6 mV (n= 17) with a slope factor (k) of 5.5 ± 0.3 mV. KChIP2c shifted the relationship to more positive potentials; however, the V1/2 and k for Kv4.3 inactivation were not significantly altered when Kv4.3 was coexpressed with KChIP2e (V1/2=–51.0 ± 0.4 mV, k= 4.9 ± 0.1 mV, n= 14) or KChIP2f (V1/2=–49.9 ± 0.7 mV, k= 5.2 ± 0.2 mV, n= 10). Expression of a 10-fold excess of KChIP2e (1.5 ng Kv4.3, 15 ng KChIP2e cRNA) that resulted in a strong reduction in current amplitudes (Fig. 3F) also did not cause a shift in the voltage dependence of Kv4.3 inactivation (Fig. 4D). Thus, unlike previously described KChIP2 isoforms , KChIP2 isoforms e and f had no effect on the voltage dependence of Kv4.3 inactivation. The effects of KChIP2 isoforms on the properties of Kv4.3 channel inactivation are summarized in Table 2.
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Kv4.3 amplitude was enhanced by coexpression with KChIP2g (Fig. 5A and B). At +40 mV, peak outward current was increased by a factor of 1.96 ± 0.30 (n= 12) compared to Kv4.3 alone (Fig. 5C). KChIP2g also slowed the onset of Kv4.3 inactivation in a voltage-independent manner (Fig. 5D). Fitting the first 200 ms of the inactivating currents to a mono-exponential function, the time constant of Kv4.3 inactivation at +40 mV was 69 ± 3 ms (n= 35) and was increased by coexpression with KChIP2g to 127 ± 7 ms (n= 13). Because slowing of inactivation was pronounced for KChIP2g, we also analysed the influence of this isoform on the slow time component of inactivation during the 1.5 s voltage steps. KChIP2g slowed the fast component of inactivation but had only a minor effect on the rate of slow inactivation (Fig. 5E). KChIP2g also increased the relative contribution of the fast component of Kv4.3 channel inactivation (Fig. 5F). In contrast to the effects on the onset of Kv4.3 inactivation, KChIP2g accelerated the recovery from inactivation (Fig. 5G). At –90 mV, recov was 220 ± 13 ms (n= 30) for Kv4.3 alone compared to 92 ± 8 ms (n= 8) for Kv4.3/KChIP2g. Thus, like KChIP2c, coexpression of KChIP2g increased the magnitude, slowed the onset of inactivation and accelerated the recovery from inactivation of Kv4.3 current. However, whereas KChIP2c shifted the voltage dependence of Kv4.3 inactivation to more positive potentials (Fig. 4C), KChIP2g had the opposite effect (Fig. 5H, Table 2) and shifted the V1/2 for inactivation by –24 mV to –57.9 ± 0.4 mV (n= 8).
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Reduced current amplitudes of Kv4.3 channels by KChIP2e could result from altered gating properties (lack of channel opening, reduction in single channel conductance, or open probability) or reduced surface expression. To test whether the reduction in Kv4.3 current amplitudes by KChIP2e is paralleled by a reduction in surface expression, an HA epitope was inserted in the S3–S4 linker of the short Kv4.3 isoform (see Methods). This channel (Kv4.3-HA) inactivated at a more negative potential (V1/2=–118.0 ± 1.1 mV; slope factor, k= 8.36 ± 0.75; n= 8) than WT Kv4.3 channels, but when currents were elicited from a more negative holding potential, currents were of similar magnitude to WT channels. Coexpression of Kv4.3-HA with KChIP2e in a 1 : 10 ratio (w/w) reduced relative current amplitudes from 1.0 ± 0.15 to 0.3 ± 0.08 (n= 9). The chemiluminescence signal (in RLU) of oocytes expressing Kv4.3-HA with KChIP2e (1 : 10 ratio w/w) was also reduced when compared with Kv4.3-HA (Fig. 6). The relative surface expression of protein was increased 1.90 ± 0.15 fold (n= 12) for coexpression with KChIP2c and it decreased by the factor 0.25 ± 0.06 (n= 12) for coexpression with KChIP2e. The reduction of surface expression of HA-tagged Kv4.3 short channels is consistent with the current reduction observed by this KChIP2 isoform. These data suggest that the reduction of current amplitude caused by coexpression of Kv4.3 and KChIP2e was primarily caused by reduction of surface expression and not altered gating or single channel properties.
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Discussion |
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Regardless of the possible physiological relevance of the various KChIP2 isoforms to native Ito,f, characterization of these isoforms can provide insights into the structural basis of KChIP2 modulation of Kv4.3. All the alternatively spliced KChIP2 isoforms studied here are missing exons 2 and 3. KChIP2c has no other structural changes relative to KChIP2a or 2b (Fig. 1). In addition, isoforms 2e and 2f have an alternative exon 10 and isoform 2g has an alternative exon 1. Finally, isoform 2f is the same as isoform 2e, except that it also lacks exon 7. Thus, for purposes of comparison, KChIP2c is a useful standard basis of reference. The absence or alternative splicing of specific exons can be correlated with some, but not all, of the differential effects of a KChIP2 isoform on Kv4.3. First, KChIP2e reduced the magnitude of Kv4.3, accelerated the onset of inactivation and slowed the recovery from inactivation, effects opposite to all the other isoforms. The only structural difference between KChIP2c and KChIP2e is the alternative exon 10 of KChIP2e. This alternative splicing in the C-terminus strongly reduces the surface expession of Kv4.3. Alternative splicing of exon 10 cannot exclusively explain these findings because KChIP2f has the same exon 10 as KChIP2e but increased Kv4.3 amplitude, albeit to a lesser extent than the KChIP2c or g. However, KChIP2f had no effect on the recovery from inactivation and only slightly slowed its onset, implicating a potentially important role for exon 7 in these effects. Second, the presence of an alternative exon 10 in isoforms 2e and 2f was associated with a loss of the typical effect (positive shift in V1/2) on channel gating associated with inactivation, whereas an alternative exon 1 (KChIP2g) caused the voltage dependence of Kv4.3 inactivation to be shifted in the negative direction. Patel et al. (2002b) demonstrated the importance of the C-terminus in mediating KChIP2 effects on the rates for onset and recovery from inactivation. The minimal KChIP2d isoform they reported contained only exons 8–10 but slowed the rate of inactivation and accelerated the recovery from inactivation of Kv4.3 (Patel et al. 2002b). Mutations in the EF-hand of exon 9 did not change the ability of KChIP2d to speed the recovery from inactivation (Patel et al. 2002b). Although findings with KChIP2d raise questions about the functional importance of the N-terminus in modulating Kv4 currents (Patel et al. 2002b), other findings support such a role. These include (1) the shift in the voltage dependence of inactivation by KChIP2c being more pronounced compared to KChIP2b, (2) the reversed shift in voltage dependence of inactivation induced by KChIP2g, and (3) the report of an N-terminal alternatively spliced KChIP4 isoform that prevents A-type inactivation of Kv4 (Holmqvist et al. 2002). These findings highlight the relevance of the N-terminus in modulating the rate of Kv4 inactivation and the voltage dependence of inactivation.
The novel KChIP2 isoforms reported here increase the potential functional diversity of transient outward (A-type) currents. Moreover, KChIP2e and KChIP2f demonstrate the importance of the C-terminus in influencing current density, and the rates of inactivation and recovery from inactivation of Kv4. Results with KChIP2g demonstrate that regions other than the C-terminus are required for functionality and that the N-terminus plays an important role in modulating the voltage dependence of inactivation. Evaluation of the physiological relevance of these isoforms in determining the properties of Ito,f in different regions of the brain and heart under normal conditions and in disease is the main challenge for future studies.
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 S. Koyama and S. B. Appel A-type K+ Current of Dopamine and GABA Neurons in the Ventral Tegmental Area J Neurophysiol, August 1, 2006; 96(2): 544 - 554. [Abstract] [Full Text] [PDF]
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 C. Fiset and W. R. Giles Transmural Gradients of Repolarization and Excitation-Contraction Coupling in Mouse Ventricle Circ. Res., May 26, 2006; 98(10): 1237 - 1239. [Full Text] [PDF]
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A. S. Barth and S. Kaab MAPK = Mitogen-Activated Protein KChIP2?: Unraveling Signaling Pathways Controlling Cardiac Ito Expression Circ. Res., February 17, 2006; 98(3): 301 - 302. [Full Text] [PDF]
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 V. Salvador-Recatala, W. J. Gallin, J. Abbruzzese, P. C. Ruben, and A. N. Spencer A potassium channel (Kv4) cloned from the heart of the tunicate Ciona intestinalis and its modulation by a KChIP subunit J. Exp. Biol., February 15, 2006; 209(4): 731 - 747. [Abstract] [Full Text] [PDF]
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S. P. Patel and D. L. Campbell Transient outward potassium current, 'Ito', phenotypes in the mammalian left ventricle: underlying molecular, cellular and biophysical mechanisms J. Physiol., November 15, 2005; 569(1): 7 - 39. [Abstract] [Full Text] [PDF]
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G.-L. Wang, G.-X. Wang, S. Yamamoto, L. Ye, H. Baxter, J. R Hume, and D. Duan Molecular mechanisms of regulation of fast-inactivating voltage-dependent transient outward K+ current in mouse heart by cell volume changes J. Physiol., October 15, 2005; 568(2): 423 - 443. [Abstract] [Full Text] [PDF]
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 J. M. Nerbonne and R. S. Kass Molecular Physiology of Cardiac Repolarization Physiol Rev, October 1, 2005; 85(4): 1205 - 1253. [Abstract] [Full Text] [PDF]
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 K. J. Rhodes, K. I. Carroll, M. A. Sung, L. C. Doliveira, M. M. Monaghan, S. L. Burke, B. W. Strassle, L. Buchwalder, M. Menegola, J. Cao, et al. KChIPs and Kv4 {alpha} Subunits as Integral Components of A-Type Potassium Channels in Mammalian Brain J. Neurosci., September 8, 2004; 24(36): 7903 - 7915. [Abstract] [Full Text] [PDF]
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