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Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Colima, Mexico
Submitted 14 October 2006; accepted in final form 5 May 2007
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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8 s) and stronger (61%). Modulation of IKV was disrupted by the AT1 receptor-antagonist losartan but not by the AT2-antagonist PD123319. IKV enhancement was reduced by the G-protein inhibitor GDP-
-S, whereas current modulation remained unaltered after cell treatment with pertussis toxin. The peptidergic modulation of IKV was severely disrupted when internal ATP was replaced by its nonhydrolyzable analogue AMP-PNP. Angio II enhanced IKV and further reduced the stimulatory action of a muscarinic agonist on IKV. Likewise, the muscarinc agonist enhanced IKV and occluded the effect of Angio II on IKV. We have also found that the protein kinase C activator PMA enhanced IKV, thereby mimicking and further attenuating the action of Angio II on IKV. These results suggest that AT1 receptors by coupling to pertussis toxin–insensitive G proteins, stimulate an ATP-dependent and PKC-mediated pathway to modulate IKV. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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). Blood pressure is long-term regulated by a complex interaction between the SNS and the rennin–angiotensin system, involving feedback mechanisms that in general tend to reinforce their pressor effects. Thus stimuli such as hypotension or hyposmolality trigger the synthesis of angiotensin II (Angio II), which directly contracts vascular smooth muscle cells and enhances renal sodium uptake. Besides, circulating Angio II elicits positive feedback on SNS either directly by stimulating norepinephrine (NE) release from sympathetic ganglionic neurons (Boehm and Kubista 2002; Dendorfer et al. 2002) or by the regulation of several nuclei within the CNS that regulate sympathetic outflow. For instance, Angio II enhances the firing frequency of action potentials in neurons from the subfornical organ (Ono et al. 2001), median preoptic nucleus (Bai and Renaud 1998), hypothalamic paraventricular nucleus (Wang et al. 1997), and pacemaker cells from the rostral ventrolateral medulla, which provide the major excitatory drive to sympathetic preganglionic neurons (Li and Guyenet 1996).
Little is known with respect to the putative presynaptic mechanisms responsible for facilitation of NE release from postganglionic nerve terminals to sympathetically innervated tissues (Boehm and Kubista 2002). Most of the stimulatory effects of Angio II might originate at the somatodendritic membrane of sympathetic ganglionic cells because of the presence of dense specific Angio II binding sites at that cell compartment, as has been shown in neurons from the superior cervical ganglion (SCG) or stellate ganglion (Castrén et al. 1987; Strömberg et al. 1991). Indeed, early microelectrode studies carried out in SCG neurons show that Angio II produces a slow membrane depolarization, leading to repetitive spike discharges (Brown et al. 1980). Therefore Angio II mimics the strong muscarinic-mediated excitatory action of acetylcholine (ACh) released from the preganglionic motoneuron nerve terminals to sympathetic ganglionic cells (Brown et al. 1980), suggesting that ACh and Angio II have similar roles regulating the excitability and metabolism of SCG sympathetic neurons. Indeed, Angio II and muscarinic agonists by stimulating AT1 and M1 receptors respectively, inhibit both the M-type K+ current (M-current) and the N-type Ca2+ current (ICaN) (Hamilton et al. 1997; Shapiro et al. 1994; Zaika et al. 2006). In addition, stimulation of these receptors activates the inositol phospholipid metabolism (del Rio et al. 1999; Strömberg et al. 1991). Recently we found that an M2/4 muscarinic receptor enhances the SCG delayed rectifier K+ current IKV (Cruzblanca 2006). In view of the close parallelism between the cellular actions of Angio II and muscarinc receptors, we sought here whether IKV was modulated by Angio II. We found that stimulation of the AT1 receptor enhances IKV current density. Besides, our results suggest that in SCG neurons the AT1 receptor couples to different signaling pathways to modulate M-current and IKV. Some of these results have appeared in preliminary form as an abstract (Cruzblanca-Hernandez et al. 2005).
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METHODS |
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Electrophysiological experiments were done in cultured SCG neurons taken from juvenile (2- to 4-wk-old) Sprague–Dawley or Wistar rats. Neurons were dissociated and cultured following the method by Cruzblanca et al. (1998). To identify the G
subunits expressed by SCG neurons, standard single-cell RT-PCR analysis was carried out as indicated in the supporting on-line material section.1
Electrophysiological recording
Whole cell patch-clamp recordings of IKV, M-current, or ICaN were done with a List EPC-7 amplifier and seals were obtained with patch pipettes with 1- to 2-M
resistance. The resulting steady series resistance after 2 min of seal breakthrough was 3–4 M. Voltage command pulses and K+ current records were generated and acquired (sampling rate, 5 kHz) using a 12-bit interface (Indec Systems, Sunnyvale, CA). Membrane currents were low-pass filtered at 1 kHz and analyzed using BASIC-FASTLAB (Indec Systems) and Sigma Plot (SPSS, Chicago, IL) programs. The M-current was recorded with the standard external solution; M-channels were fully activated by setting the holding potential (Vh) at –25 mV and further deactivated by 500-ms pulses from –25 to –60 mV, every 4 s. The amplitude of the M-current and its percentage of inhibition were measured as described (Cruzblanca et al. 1998). For IKV isolation neurons were held at –50 mV to fully inactivate the IA K+ current (Wang and McKinnon 1995) and Cd2+ was added to the standard external solution to block voltage-activated Ca2+ currents and Ca2+-activated K+ currents. Thereafter IKV was elicited by 100-ms command pulses from –50 to 40 mV, in 10- to 20-mV steps. The amplitude of IKV and its modulation were measured as described (Cruzblanca 2006). ICaN was recorded with the standard external solution and by cell dialysis with a Cs-based pipette solution. ICaN was elicited by a 10-ms command pulse from a Vh of –80 to 10 mV, every 4 s. Membrane voltages were corrected on-line for a –2-mV junction potential (standard internal solution); statistics are given as means ± SE. Sample means were compared using Student's t-test and differences were considered significant at P < 0.05.
Solutions
Composition of the modified Hank's solution was (in mM): 137 NaCl, 5.4 KCl, 0.44 KH2PO4, 0.34 NaH2PO4, 5 HEPES, and 5 glucose (pH = 7.4). SCG cells were transferred to a recording chamber (400 µl) and bathed (2.8 ml/min) with the appropriate external solution. For M-current recording the standard external solution was (in mM): 160 NaCl, 2.5 KCl, 2 CaCl2, 1 MgCl2, 10 HEPES, 8 glucose, and 0.5 µM tetrodotoxin (TTX). The pH was adjusted to 7.4 with NaOH. For IKV recording Cd2+ (200 µM) was added to the external saline. Solution changes were accomplished in approximately 10 s and the experiments were done at 25°C.
Composition of the standard pipette internal solution was (in mM): 175 KCl, 5 MgCl2, 5 HEPES, 0.1 BAPTA, 3 K2ATP, 0.1 Na-GTP, and 0.08 leupeptin (pH = 7.4, adjusted with KOH). For ICaN recording the internal solution was (in mM): 175 CsCl, 5 MgCl2, 5 HEPES, 0.1 BAPTA, 3 Na2ATP, 0.1 Na-GTP, and 0.08 leupeptin (pH = 7.4, adjusted with CsOH). When cell dialysis with a test molecule from the patch pipette was required [guanosine 5'-O-(2-thiodiphosphate) (GDP--S) or 5'-adenylyl-,
-imododiphosphate (AMP-PNP)], we waited for approximately 8-min dialysis before beginning membrane current recordings. To avoid systematic bias, control and test measurements were alternated within each set of experiments.
Drugs
Reagents were obtained as follows: pertussis toxin (PTX) (List Biological Labs, Campbell, CA); collagenase I, poly-L-lysine, HEPES, Na-GTP, oxotremorine-M, and PD123319 (Sigma, St. Louis, MO); BAPTA (Molecular Probes, Eugene, OR); papain, dispase II, leupeptin, and K2-ATP (Roche Diagnostics, Mannheim, Germany); DMEM and heat-inactivated FBS (GIBCO/Invitrogen, Carlsbad, CA); TTX, Angio II, AMP-PNP, GDP--S, phorbol 12-myristate 13-acetate (PMA), and 4-phorbol (Calbiochem, La Jolla, CA). Stock solutions of AMP-PNP, GDP--S, PMA, 4-phorbol, and Na-GTP were prepared in water or DMSO, aliquoted, and kept at –20°C until use.
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RESULTS |
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In sympathetic SCG cells muscarinic agonists and Angio II inhibit both M-current and ICaN (Hamilton et al. 1997; Shapiro et al. 1994; Zaika et al. 2006), and muscarinic agonists enhance the delayed rectifier K+ current, IKV (Cruzblanca 2006). Therefore it might be possible that Angio II modulates IKV as well. Figure 1 shows that Angio II (500 nM) indeed enhanced IKV (Fig. 1A) and, as expected, inhibited M-current (Fig. 1B). In addition to the opposite effects Angio II had on these K+ currents, there were additional differences in their latency and rate of modulation (see plots in Fig. 1). The percentage of IKV mean increase was 30.4 ± 2.4% (n = 15) with a latency of 16.2 ± 0.9 s. As soon as IKV enhancement was detectable this effect developed with a time constant of 29.3 ± 2.8 s. In contrast, M-current mean inhibition was 60.9 ± 3.2% (n = 13) and the effect had a latency and time constant of approximately 8 s and 10.8 ± 0.5 s, respectively. As for IKV muscarinic modulation (Cruzblanca 2006), Angio II produced no changes in the IKV current–voltage relationship (not shown).
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To search for the identity of the Angio II receptor type modulating IKV, neurons were treated with the AT1-receptor antagonist losartan, 2 min before and throughout peptide exposure. Initially, ICaN modulation was used as a positive control to verify the potency of losartan (kindly donated by Merck) in our experimental conditions because AT1 receptor inhibits ICaN in SCG cells (Shapiro et al. 1994). As expected, losartan (2 µM) practically abolished the inhibitory effect of Angio II on ICaN (Fig. 2A, inset). In control cells (n = 5) Angio II produced an ICaN mean inhibition of 40.7 ± 5.7% (n = 5), whereas in those neurons treated with losartan, this effect was significantly (P < 0.05) reduced to 11.8 ± 0.9% (n = 4). Likewise, losartan remarkably disrupted the IKV enhancement produced by Angio II (Fig. 2A). In summary, the enhancement in IKV current density was reduced by losartan from 10.6 ± 1.5 (n = 15) to 3.9 ± 0.8 pA/pF (n = 13). To confirm that an AT1 receptor was primarily responsible for IKV modulation, a different set of neurons were treated with the AT2-selective receptor antagonist PD123319 (2 µM). We found that the mean increases in IKV current density from control and PD123319-treated cells were 11.8 ± 1.9 (n = 7) and 11 ± 1.4 pA/pF (n = 13), respectively, (Fig. 2B). Thus IKV modulation by Angio II was quite insensitive to the AT2 antagonist.
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Recent evidence indicates that AT1 receptors can couple directly to signaling molecules different from G proteins, thereby providing the structural basis for G-protein–independent activation of signaling pathways (Doan et al. 2001; Heuss and Gerber 2000; Seta et al. 2002). To assess whether IKV modulation was linked to the activation of G proteins, SCG neurons were dialyzed with the G-protein inhibitor GDP--S (2 mM in pipette). GDP--S practically abolished the Angio II-induced IKV enhancement (Fig. 3A, right) compared with those cells dialyzed with the standard GTP-containing pipette internal solution (Fig. 3A, left). In summary, the increases in IKV current density in neurons dialyzed without and with GDP--S were 10.1 ± 1.6 (n = 11) and 2.8 ± 0.8 pA/pF (n = 10), respectively, a difference that was statistically significant (P < 0.05).
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). However, in some instances this receptor also couples to PTX-sensitive G proteins to modulate neuronal ion channels (Oz et al. 2002). Thus an initial characterization of the G-protein–mediating IKV modulation consisted in identifying the G subunits expressed by SCG neurons and in determining the PTX sensitivity of IKV modulation. Single-cell RT-PCR analysis (see METHODS in the supporting on-line material) yielded cDNA fragments of the predicted size for the PTX-sensitive G subunits Go, Gi1, Gi2, and Gi3 and for the PTX-insensitive proteins Gq, G11, Gs, G12, and Gz. Besides, toxin treatment (500 ng/ml) of SCG neurons for 10 h did not disrupt IKV enhancement by Angio II (Fig. 3B). In summary, Angio II increased IKV current density in control and PTX-treated neurons by 12 ± 1.7 (n = 8) and 13.4 ± 0.9 pA/pF (n = 10), respectively. To validate these results we checked for PTX activity in our experimental conditions, by testing the well-known PTX-sensitive modulation of ICaN by somatostatin (Beech et al. 1992). As expected, PTX treatment blocked the somatostatin inhibitory effect on ICaN (Fig. 3B, inset). ATP is required for IKV modulation by Angio II
Previously we found that IKV modulation by the muscarinic agonist oxotremorine-M (Oxo-M) is reduced when internal ATP is replaced by its nonhydrolyzable analogue AMP-PNP (Cruzblanca 2006). Therefore we asked whether ATP might also be required for IKV peptidergic modulation. Thus cells were dialyzed for about 8 min with an internal solution containing AMP-PNP, instead of ATP. The Angio II–induced enhancement of IKV was remarkably reduced in the presence of this nonhydrolyzable nucleotide (Fig. 4). In summary, Angio II enhanced IKV current density by 10.8 ± 2.2 pA/pF (n = 8) in ATP-dialyzed neurons, whereas this effect was reduced to 3.1 ± 1.5 pA/pF (n = 6) in those cells dialyzed with AMP-PNP.
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The IKV enhancement by Angio II shows a strong parallelism with the muscarinic modulation of this delayed K+ current (Cruzblanca 2006), that is, both modulations are PTX insensitive and disrupted by AMP-PNP. Therefore it could be possible that the M2/4 muscarinic and AT1 receptors activate the same or similar signaling pathways to modulate IKV. This hypothesis was tested by bathing the cells sequentially with Angio II and Oxo-M, to look for additive or occlusive effects between these agonists. When Angio II was initially applied, there was an increase in IKV and on reaching its maximum peptidergic stimulation Oxo-M had no effect on IKV (Fig. 5A, left plot). Likewise, when Oxo-M was first applied, it enhanced IKV amplitude; thereafter an occlusion of the Angio II action occurred (Fig. 5A, right plot). On average, when Angio II (500 nM) and Oxo-M (1 µM) were applied alone (Fig. 5B, filled bars) the increment in IKV current density was 10.1 ± 2 (n = 8) and 16 ± 1.4 pA/pF (n = 7), respectively. Moreover, Angio II significantly reduced IKV enhancement by Oxo-M to 5.6 ± 1.5 pA/pF (n = 8), whereas Oxo-M practically occluded the Angio II effect (0.3 ± 0.2 pA/pF, n = 7) (Fig. 5B, open bars).
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The receptor- and ATP-dependent regulation of IKV might reflect a phosphorylation mechanism mediated by protein kinases. The principal biochemical effect of Angio II on SCG cells is the activation of membrane-associated phospholipase C (PLC), which thereby leads to the synthesis of inositol triphosphate (IP3) and diacylglycerol (DAG) (Delmas et al. 2005; Strömberg et al. 1991). Because in these sympathetic neurons Angio II does not cause increases of intracellular calcium ion concentration ([Ca2+]i) (Delmas et al. 2005; Shapiro et al. 1994), the DAG-PKC branch of the PLC pathway could partially account for the action of Angio II on IKV. To test this hypothesis, neurons were acutely exposed to the PKC activator PMA (30 nM), after which they were challenged with Angio II. Control experiments were done with cells exposed to 4-phorbol (30 nM), an inactive analog. The pharmacological activation of PKC produced an increase of IKV that was noticeable at membrane voltages more positive than –20 mV (Fig. 6A), as it was found either by Angio II (Fig. 1) or muscarinic agonists (Cruzblanca 2006). The PMA-induced enhancement of IKV was slow and, when Angio II was sequentially applied, this peptide produced only a slight increase of IKV (Fig. 6B). In summary, PMA increased IKV current density by 10 ± 1.1 pA/pF (n = 7), whereas 4-phorbol produced an increase of only 0.9 ± 0.5 pA/pF (n = 6) (Fig. 6C). Furthermore, when cells were exposed only to Angio II, this peptide enhanced IKV by 11.1 ± 1.4 pA/pF, (n = 8), whereas in those cells previously treated with PMA the effect of Angio II was significantly (P < 0.05) reduced to 2.5 ± 1.2 pA/pF (n = 7) (Fig. 6C).
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). Thus to continue exploring the potential participation of PKC on IKV modulation, SCG neurons were incubated for 8 h with 30 nM PMA. Thereafter, PMA was removed from the culture medium before the patch-clamp experiments were carried out. It was found that long-term treatment with PMA reduced the Angio II–induced enhancement of IKV from 11.5 ± 1 (n = 7) to 3.8 ± 1.2 pA/pF (n = 8), a statistically significant difference (P < 0.05). |
DISCUSSION |
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; Ono et al. 2001), a resting leakage K+ conductance (Li and Guyenet 1996; Oz and Renaud 2002), and/or the IA K+ current (Li and Ferguson 1996). In comparison, less is known about the effects of Angio II on sympathetic ion channels. In the SNS, the best documented effects of Angio II concerns the inhibition of ICaN and M-current in SCG neurons (Hamilton et al. 1997; Shapiro et al. 1994; Zaika et al. 2006). In the present study we found that in these sympathetic cells Angio II modulates the delayed rectifier K+ current IKV as well (Fig. 1). IKV enhancement was completely reproducible among SCG cultures, thereby contrasting with the reported diverse effects of Angio II on delayed rectifier currents from CNS neurons, including lack of effect (Li and Ferguson 1996), or either increase (Zhu et al. 1998) or decrease (Sumners et al. 1996). The diverse effects of Angio II on neuronal delayed rectifier K+ currents could be partially explained 1) on the basis of the molecular identity of their respective K+ channel subunits or 2) by the different Angio II receptor type and its signaling pathway activated as well. In SCG cells, the peptidergic modulation of IKV was selectively attenuated by the AT1 antagonist losartan (Fig. 2), suggesting that the AT1 receptor underlies most of the IKV enhancement. These results are in agreement with the presence of abundant specific binding sites for AT1 receptors at the somatodendritic membrane of SCG neurons (Castrén et al. 1987; Strömberg et al. 1991).
Commonly G proteins transduce the membrane message resulting from the activation of AT1 receptors. However, in some instances that type of Angio II receptor can directly couple to different transducer molecules, thereby providing the structural basis for G-protein–independent signaling (Heuss and Gerber 2000). For example, in CHO cells AT1 receptors elicit a Gq-mediated increase of intracellular Ca2+ and the parallel activation of the Jak2/STAT1 pathway (Doan et al. 2001). However, a carboxyl-terminal receptor mutation that disrupts its coupling to Gq abolishes the Ca2+ signal but it does not prevent activation of the Jak/STAT pathway (Doan et al. 2001). Similarly, a different AT1 mutant with impaired G-protein coupling retains its capacity to activate the Ras-ERK pathway in a Src-dependent manner (Seta et al. 2002) a tyrosine kinase that has been implicated in G-protein–dependent or –independent modulation of ion channels (Gamper et al. 2003; Heuss et al. 1999). Therefore it was unavoidable to examine whether IKV modulation was linked to G-protein activation. Given that GDP--S, a general G-protein inhibitor, prevented the effect of Angio II on IKV (Fig. 3A), we conclude that G proteins mediate the AT1-receptor–induced enhancement of IKV. We thus further examined the family type of the G protein because AT1 receptors, despite commonly coupling to members of the Gq family (Alexander et al. 2006), in some instances PTX-sensitive G proteins such as Go or Gi can mediate the actions of AT1 receptors on ion channels (Oz and Renaud 2002). Given that SCG neurons expressed significant transcripts of the PTX-sensitive G subunits Go, Gi1, Gi2, and Gi3, it was necessary to test for PTX sensitivity of IKV modulation. Our results showed that PTX did not disrupt the modulation of IKV (Fig. 2B). Therefore we conclude that AT1 receptors couple to PTX-insensitive G proteins to enhance IKV. Further molecular, combined with patch-clamp, studies are required to identify the precise PTX-insensitive G protein(s) underlying the angiotensinergic modulation of IKV.
It has long been recognized that Angio II mimics most of the muscarinic-mediated excitatory actions of ACh on sympathetic neurons (Boehm and Kubista 2002; Brown et al. 1980), suggesting that Angio II and muscarinic receptors activate similar signaling pathways to modulate an exclusive set of ionic currents. For SCG neurons the endogenous ionic currents modulated by AT1 receptors are the M-current, ICaN (Hamilton et al. 1997; Shapiro et al. 1994; Zaika et al. 2006), and, as is reported here, IKV as well. The signaling pathway and mechanism for the M1-mediated inhibition of M-current, which have been recently elucidated, involve a Gq-activated PLC that hydrolyzes PIP2 and its membrane depletion closes M-channels (Suh and Hille 2002; Winks et al. 2005; Zhang et al. 2003). Evidence obtained in CHO cells heterologously expressing both the AT1 receptor and M-channels suggests that the PIP2-depletion mechanism is used by Angio II to suppress M-current as well (Zaika et al. 2006). On the other hand, it is a matter of dispute whether ICaN modulation by the M1 receptor is mediated by the same PIP2-depletion signal or whether it is mediated by arachidonic acid (Gamper et al. 2004; Liu and Rittenhouse 2003). In comparison, our results suggest that a mechanism of phosphorylation mediated by the DAG-PKC branch of the PLC pathway largely contributes to the modulation of IKV by the AT1 receptor. This conclusion is supported, because: 1) modulation of IKV was disrupted by the nonhydrolyzable ATP analog AMP-PNP (Fig. 4); 2) the PKC activator PMA mimicked and occluded the effect of Angio II on IKV (Fig. 6); and 3) the long-term incubation of PMA, which downregulates PKC (Nishizuka 1988), reduced IKV modulation. The potential participation of protein kinases (including PKC) is also consistent with the fact that Angio II enhanced IKV with a time course that was twice as slow as that for M-current inhibition (Fig. 1), which is assumed to be mediated by depletion of PIP2 (Zaika et al. 2006), whereas IKV modulation probably requires additional biochemical steps.
It has long been known that Angio II directly enhances sympathetic neuron excitability (Brown et al. 1980). In SCG cells this effect is thought to be partially mediated by the inhibition of M-current, resulting in a slow depolarization, reduced spike threshold, and reduced spike frequency adaptation (Zaika et al. 2006). In sympathetic neurons a sustained high-frequency pattern of action potentials is required to enhance the probability of transmitter release because in these nerve cells it appears to be lower (1–3%) (Boehm and Kubista 2002). Given that changes in M-current amplitude do not modify action potential waveforms (Lechner et al. 2003), how is the high-frequency firing maintained? We propose that the Angio II–mediated enhancement of IKV stabilizes tonic firing by accelerating action potential repolarization and increasing the fast spike afterhyperpolarization, thereby reducing the fraction of Na+ channels inactivated during each action potential. Current-clamp experiments and modeling are needed to test this hypothesis. However, in partial support of this proposal are the findings that during SCG tonic firing, partial block of IKV slows spike repolarization and reduces spike afterhyperpolarization and thus the amplitude of spikes progressively decreases (Malin and Nerbonne 2002).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 The online version of this article contains supplemental data. 
Address for reprint requests and other correspondence: H. Cruzblanca, Centro Universitario de Investigaciones Biomédicas, Universidad de Colima, Av. 25 de Julio 965, Col. Villas San Sebastián, Colima, Colima 28045, Mexico (E-mail: cruzblan{at}cigc.ucol.mx)
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSACKNOWLEDGMENTSREFERENCES |
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