© 2000 American Heart Association, Inc.
Cellular Biology |
Inhibition by Protein Kinase C of the KNDP Subtype of Vascular Smooth Muscle ATP-Sensitive Potassium Channel
From the Smooth Muscle Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada. Current address of P.E.L. is Department of Pharmacology, University of Alberta, Edmonton, AB, Canada.
Correspondence to Dr William C. Cole, Smooth Muscle Research Group, Faculty of Medicine, University of Calgary, 3330 Hospital Dr, NW, Calgary, Alberta, Canada, T2N 4N1. E-mail wcole{at}ucalgary.ca
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Abstract |
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Abstract—ATP-sensitive K+ channels (KATP) contribute to the regulation of tone in vascular smooth muscle cells. We determined the effects of protein kinase C (PKC) activation on the nucleoside diphosphate–activated (KNDP) subtype of vascular smooth muscle KATP channel. Phorbol 12,13-dibutyrate (PdBu) and angiotensin II inhibited KNDP activity of C-A patches of rabbit portal vein (PV) myocytes, but an inactive phorbol ester was without effect, and pretreatment with PKC inhibitor prevented the actions of PdBu. Constitutively active PKC inhibited KNDP in I-O patches but was without effect in the presence of a specific peptide inhibitor of PKC. PdBu increased the duration of a long-lived interburst closed state but was without effect on burst duration or intraburst kinetics. PdBu treatment inhibited KNDP, but not a 70-pS KATP channel of rat PV. The results indicate that the KNDP subtype of vascular smooth muscle KATP channel is inhibited by activation of PKC. Control of KNDP activity by intracellular signaling cascades involving PKC may, therefore, contribute to control of tone and arterial diameter by vasoconstrictors. (Circ Res. 2000;87:112-117.)
Key Words: vascular smooth muscle • potassium channel • protein kinase C
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Introduction |
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ATP-sensitive K+ channels (KATP), acting in concert with at least 3 other K+ channels, including delayed rectifier, large-conductance Ca2+-activated, and inward rectifier K+ channels, play an important role in the control of membrane potential and tone in vascular smooth muscle.1 Variations in membrane potential are critical for regulating the influx of Ca2+ via L-type Ca2+ channels and thereby controlling the level of intracellular free Ca2+, activation of myosin light chain kinase, and contractile filament interaction. Vasoactive agonists, which produce dilation or constriction of resistance vessels, influence vascular smooth muscle tone in part by affecting the activity of K+ channels.1 However, our understanding of the specific signal-transduction pathways involved, the identities of the K+ channels affected, and the circumstances under which different K+ channels contribute to the control of arterial diameter by vasoactive agonists is incomplete.2
Several vasoconstrictors affect K+ channel activity in vascular myocytes. For example, voltage-clamp studies provide evidence for the regulation of delayed rectifier,3 4 5 6 Ca2+-activated,7 8 and KATP9 currents. Signal-transduction pathways involving the activation of protein kinase C (PKC) were implicated in the response to vasoconstrictors through the use of selective activators and inhibitors of PKC3 4 6 9 ; inhibition of delayed rectifier K+ current by angiotensin II or endothelin-1 was mimicked by diacylglycerol analogs or phorbol esters and prevented by PKC inhibitors.3 4 6 KATP currents of arterial myocytes are similarly affected by agonists and pharmacological manipulations that modulate PKC.1 9 However, the identity of the vascular smooth muscle KATP channel(s) regulated by PKC is unknown.
In contrast to KATP channels of cardiac myocytes (80 pS),10 the channels of vascular myocytes possess a range of unitary conductance from 5 to >100 pS.9 The reasons for this variability are obscure, but a strong case has been made, by Beech et al,11 12 and Zhang and Bolton,13 14 for the expression of multiple KATP subtypes. The following 2 KATP channels were identified in rat portal vein (PV; asymmetrical KCl conditions): (1) a 22-pS channel that was inactive in the absence of MgATP, but activated by nucleoside diphosphates (the KNDP subtype), and (2) a 50-pS cardiac-like KATP channel referred to as the large conductance or LK subtype.14
We tested the hypothesis that the KNDP subtype is the vascular KATP channel modulated by PKC using C-A and I-O patches of freshly dispersed rabbit and rat PV myocytes. PKC activity of intact myocytes was modulated by exposure to angiotensin II or to phorbol ester in the absence or presence of selective PKC inhibitors. I-O patches were exposed to a constitutively active proteolytic fragment of PKC, and the effect on KNDP activity was determined. Our results provide the first evidence for a modulation by PKC of the KNDP subtype, but not the LK channel of vascular smooth muscle.
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Materials and Methods |
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Rabbit and rat myocytes were isolated15 and studied by C-A and I-O patch clamp16 at 20°C to 22°C. Pipette and bath solutions, respectively, contained (in mmol/L) KCl 140, CaCl2 1, MgCl2 1, glucose 5.5, HEPES 10, and iberiotoxin 0.0002 and KCl 140, MgCl2 2.3, glucose 10, EGTA 1, and HEPES 10 (pH 7.4 with KOH). For I-O patches, the bath had MgATP (0, 0.1, or 1 mmol/L) and MgADP (0 or 0.5 mmol/L). PdBu (50 nmol/L), 4
-phorbol-12,13-didecanoate (PdDe) (50 nmol/L), chelerythrine
(1 µmol/L), 2,4-dinitrophenol (DNP) (50 µmol/L),
2-deoxy-D-glucose (2-DG) (10 mmol/L), and
glibenclamide (3 µmol/L) were obtained from Sigma. Pinacidil,
calphostin C (1 µmol/L), and iberiotoxin were purchased from
Calbiochem-Novabiochem Corp. Constitutively active PKC (PKM; 20
nmol/L)17 and PKC(19-31)18 (5 µmol/L)
were prepared as previously described. Paired Student t test
and ANOVA followed by Bonferroni post hoc test were used for single and
multiple comparisons, respectively. A level of P<0.05 was
statistically significant. An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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Identification of KNDP Channels
Initial experiments identified the KATP channels of rabbit PV myocytes as the KNDP subtype.11 12 13 14 Figure 1
shows KNDP
induced by pinacidil and blocked by glibenclamide, as well as a unitary
current-voltage (I-V) relation. Similar results were
obtained in 2 other patches, and the average changes in the
product of the number of channels (N) and mean open probability
(PO) (NPO) are given in Table 1
online (available at http://www.circresaha.org).
KNDP activity was characterized by bursts of
transitions separated by relatively long-duration, interburst
intervals. Pinacidil-induced KNDP activity was
apparent in 75% of C-A patches and was stable for >15 minutes; no
change in NPO occurred in 15 to 30 minutes (0.619±0.187
versus 0.426±0.144 at 2 to 5 minutes; n=5; P>0.05). With
140 mmol/L KCl in the pipette solution, the unitary currents of
C-A patches had a slope conductance of 41±0.9 pS (n=10) (Figure 1), but a slightly lower value of 37.3±1.5 pS (n=7) was
obtained for I-O patches (symmetrical 140/140 mmol/L transmembrane
KCl gradient). In contrast to cardiac KATP and
vascular LK channels, KNDP channels
require intracellular MgATP for activity.14 Figure 1 shows that patch excision into MgATP-free solution failed to
activate the 40-pS channels, and when
KNDP channels were activated with
pinacidil in the C-A configuration, excision caused a loss of activity.
Similar results were obtained from 3 and 5 additional patches,
respectively. These properties are consistent with those
reported previously.14
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Inhibition of KNDP by Phorbol Ester or Angiotensin
II
To assess the effect of PKC on KNDP,
myocytes were treated with PdBu in the presence of pinacidil (Figure 2). PdBu caused
KNDP activity to decline, and NPO
values for KNDP in PdBu and pinacidil were
significantly lower than pinacidil alone (Table 1
online; available at
http://www.circresaha.org). Additionally, exposure to PdBu of 3
myocytes exhibiting background KNDP activity also
caused a decline in activity, and, in 3 patches exposed to pinacidil
and PdBu and held for a sufficiently long period to permit washout of
PdBu, complete reversibility of the decline in activity was observed
(data not shown).
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Angiotensin II is known to activate PKC in
smooth muscle cells,19 to inhibit delayed rectifier
K+ channels,4 and to cause a decrease in
KATP current of mesenteric arterial
myocytes via PKC.20 In the presence of
angiotensin II, pinacidil-induced
KNDP activity of C-A patches of rabbit PV
myocytes was inhibited (Figure 3); on
average in 4 patches, application of angiotensin II caused
a decline in NPO of >10-fold (Table 1 online; available at
http://www.circresaha.org).
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Effect of Inactive Phorbol Ester and PKC Inhibitors
To control for possible non–PKC-dependent effects of PdBu,
2 different approaches were used, as follows: myocytes were (1) exposed
to the inactive phorbol ester PdDe or (2) pretreated with a PKC
inhibitor, chelerythrine or calphostin C, before treatment
with PdBu (Figure 4). PdDe failed to affect KNDP
activity after more than 20 minutes of treatment (Figure 4). In PdBu,
NPO declined within 10 minutes in all patches, but no
change in activity was observed in PdDe within at least 12 minutes of
recording. Figure 4C shows a representative example of the effect of
pretreatment with calphostin C for 10 to 15 minutes on KNDP
activity. No effect on background or pinacidil-induced activity was
noted, and subsequent exposure to PdBu did not alter KNDP
activity. A similar lack of effect of PdBu was observed after
pretreatment with chelerythrine. See Table 1 online (available at
http://www.circresaha.org) for average NPO values
with or without PKC inhibitor.
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Effect of PKC Activation on KNDP Channel
Kinetics
Figure 2 shows representative examples of
bursts and dwell-time histograms for the open state. There was
no difference in intraburst kinetics in the absence and presence of
pinacidil; mean open and closed times were 2.55±0.14 and 0.43±0.01 ms
in the absence of pinacidil and 2.56±0.08 and 0.41±0.02 ms in the
presence of pinacidil, respectively. PdBu was also without effect: mean
open and closed times after 5 minutes were 2.14±0.05 and 0.39±0.03 ms
for basal and 2.29±0.07 and 0.43±0.01 ms in pinacidil
(P>0.05 in all cases).
To determine the effect of PKC on burst kinetics, >100 bursts
were analyzed in each condition from 3 patches. The
Table shows that burst duration and interburst interval
were longer and shorter, respectively, in pinacidil compared with
background KNDP activity. In both cases, however,
PKC activation caused a significant increase in interburst interval,
but burst duration was unaffected
(Table).
Effect of Constitutively Active PKC
To directly assess the effect of PKC on
KNDP, patches were excised into bath solutions
containing MgATP (0.1 or 1 mmol/L). In contrast to the absence of
KNDP activity in MgATP-free solution (Figure 1), patches excised into solutions containing 1 mmol/L
MgATP displayed robust activity, which was stable for >20 minutes
without rundown (data not shown) and further enhanced by exposure to
0.1 mmol/L MgATP (Figure 5A). Figure 5 shows that PKM in the presence of the specific peptide
inhibitor, PKC(19-31), failed to affect channel activity,
but NPO was decreased by PKM alone. Similar
results with PKM and PKC(19-31) were obtained for 3 additional I-O
patches: on average, PKM caused a 63% decline in
NPO to 0.857±0.041 from 2.678±0.047 in 0.1
mmol/L MgATP (P<0.05). Reversibility was observed in 2 of 3
patches (eg, Figure 5D).
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NPO of cardiac KATP
channels was found to increase with PKM treatment in the presence of
1 mmol/L compared with a decrease in 0.05 mmol/L
MgATP.21 For this reason, we also treated 6 I-O patches
with PKM in the presence of 1 mmol/L MgATP and 0.5 mmol/L
MgADP. Figure 5B shows that PKM inhibited the channels in the
presence of 1.0 mmol/L MgATP; in 6 patches,
NPO was 0.296±0.087 in ATP/ADP alone and
application of PKM and PKC(19-31) was without effect
(NPO=0.295±0.016), but PKM alone decreased
NPO to 0.091±0.047 (P<0.05). The
effect of PKM was fully reversed in 3 of 6 patches during washout
(respective NPOs of 0.426±0.134 before,
0.137±0.089 during, and 0.449±0.131 after PKM for these myocytes).
Variability in reversibility on washout of PKM may be due to loss or
inactivation of phosphatase activity after patch excision.
Effect of PKC on KATP of Rat PV
We determined whether the 2 KATP
channels of rat PV were similarly modulated by PKC.
KNDP activity was seen in preliminary experiments
using pinacidil, but LK channels were not activated (data not
shown), as reported previously.14 For this reason, the
metabolic inhibitors DNP and 2-DG were used.
Figure 6A shows a
representative C-A patch recording in which
both subtypes of 40-pS (38.5±2.7; n=4 patches) and 70-pS (70.5±1.7;
n=3 patches) conductance, glibenclamide-sensitive channels were
identified. Similar results were obtained in 3 additional patches.
Treatment with PdBu in the presence of metabolic
inhibitors reduced KNDP
NPO from 0.200±0.061 to 0.035±0.019
(P<0.05) in 4 patches. However, as shown in Figure 6B, the 70-pS channels were unaffected by PdBu. Similar results
were obtained in 2 additional patches containing only the 70-pS channel
and in 3 patches in which both subtypes were present.
NPO values were 0.077±0.027 and 0.094±0.036
(P>0.05) in the absence and presence of PdBu, respectively,
for the patches containing only the LK subtype. In patches containing
both subtypes, only the KNDP channels were
inhibited by PdBu (data not shown).
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Discussion |
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This study identifies the regulation by PKC of a 40-pS–conductance KNDP subtype, but not a larger-conductance, 70-pS KATP channel of vascular smooth muscle cells. The properties of the 40- and 70-pS channels studied here are consistent with those previously described.11 12 13 14 Suppression of KNDP channel activity by PKC activation was due to an increased time spent in a long-lived interburst closed state, was mimicked by treatment with angiotensin II, and was completely blocked by pretreatment with the PKC inhibitor calphostin C or chelerythrine. The decline in KNDP channel activity due to PKC activation identified in this study may account for the previously reported reduction in whole-cell KATP currents after treatment of vascular myocytes with vasoconstrictors, phorbol esters, or diacylglycerol analogs,1 and therefore, for the contribution of this conductance to the regulation of vascular smooth muscle tone via intracellular signaling cascades involving PKC.
KATP currents have been identified in a variety of vascular myocytes, and K+ channel-opening drugs induce a voltage-independent K+ current that is suppressed by glibenclamide or reductions in intracellular MgATP.9 However, the identity of the single channels involved is controversial: the variability in unitary conductance (5 to >100 pS9 ) prompted the suggestion that multiple subtypes may be expressed, but molecular biological evidence confirming the identity of the presumed KATP channels is lacking. Rat PV myocytes contain 2 glibenclamide-sensitive channels with distinct unitary conductance and sensitivities to K+ channel opening drugs, intracellular MgATP, and nucleoside diphosphates.11 12 13 14 LK channels were (1) relatively insensitive to pinacidil and glibenclamide and (2) activated in I-O patches in MgATP-free solution.14 In contrast, KNDP channels were (1) activated by pinacidil at low concentrations; (2) inactive in the absence of intracellular MgATP; and (3) activated by nucleoside diphosphates, the latter prompting their classification as KNDP channels.11 12 13 14 22 Similar channels have been observed in myocytes of several vascular and nonvascular smooth muscles.11 12 13 14 22 23 24 25 26 The properties exhibited by the channels of rabbit and rat PVs studied here are consistent with these previous reports. However, our results are the first to indicate that these subtypes also differ with respect to their modulation by PKC.
Two different approaches were taken to assess the modulation by PKC, as follows: (1) the activity of PKC of intact myocytes was manipulated pharmacologically, and (2) a constitutively active PKC, PKM, was used. PdBu and angiotensin II were used to activate PKC and were found to reduce KNDP channel activity. The possibility that nonspecific effects of phorbol ester treatment were involved was ruled out using an inactive phorbol ester, PdDe. Additionally, pretreatment with inhibitors of PKC, calphostin C or chelerythrine, having distinct structures and mechanisms of action,27 28 prevented the PdBu-induced inhibition of KNDP channel function. These data suggest that activation of PKC via ligand binding to a receptor or direct activation by a phorbol ester leads to a decline in KNDP channel activity in intact vascular myocytes.
Direct evidence for modulation of KNDP activity by PKC was obtained; PKM suppressed the activity of KNDP in I-O patches, and this inhibition was blocked by the specific inhibitor peptide of PKC(19-31). A similar inhibition of KNDP channel activity during exposure to PKM was observed with 0.1 and 1.0 mmol/L MgATP in the bath solution. This result is different from that previously reported for cardiac KATP channels, in which inhibition by PKM was observed at 0.05 mmol/L, but an increase in activity occurred at 1.0 mmol/L.18 21 Thus, the inhibition of vascular KNDP activity by PKC at physiological levels of intracellular ATP occurred via a mechanism distinct from that shown for the regulation of cardiac KATP channels.
We determined the mechanism accounting for the change in NPO using membrane patches containing single KNDP channels. KNDP channel activity exhibited bursts of transitions between the open and closed states separated by extended intervals in a long-lived closed state. The mean intraburst open and closed times were not affected by pinacidil, but burst duration and interburst intervals were longer and shorter, respectively, consistent with the previously reported modulation of KATP gating by K+ channel openers.9 Activation of PKC did not affect intraburst kinetics or burst duration, but interburst interval was significantly increased. This change provides a possible explanation for the effects of PKC-mediated phosphorylation on gating. The long-lived interburst interval is thought to reflect a transition from the open state into a closed state(s) in which ATP is bound to the channel.29 PKC-mediated phosphorylation may stabilize the channels in this interburst closed state by altering ATP binding and decreasing its dissociation. Interestingly, stimulation of cardiac KATP activity by PKC is due to a change in the stoichiometry of ATP binding,18 21 but this alteration is associated with an increase in burst duration (P. Light, unpublished data, 1999).
The exclusive presence of KNDP channels in rabbit PV,12 22 rat mesenteric artery,13 and guinea pig coronary artery30 31 suggests that their modulation can be exclusively responsible for the decline in whole-cell KATP currents by vasoconstrictors, diacylglycerol analogs, or phorbol esters via PKC.1 20 However, the presence of additional glibenclamide-sensitive KATP subtypes raises the possibility that multiple channels may be involved in some vessels. It is unlikely, however, that an inhibition of the LK subtype is involved. We base this view on the lack of effect of PKC activation on the 70-pS subtype, but marked inhibition of the 40-pS KNDP channels of rat PV myocytes. The lack of inhibition of the 70-pS LK channels by PdBu indicates that despite sharing properties with cardiac KATP subtype,14 such as conductance and relative insensitivity to pinacidil, they are not identical in terms of their modulation by PKC. Yamada et al32 and Satoh et al33 demonstrated that recombinant KATP consisting of Kir6.1 and SUR2B proteins share biophysical and pharmacological properties with KNDP channels.11 12 13 14 In contrast, cardiac KATP channels are thought to consist of Kir6.2 and SUR2A subunits.9 Thus, a difference in subunit composition likely accounts for the divergent effects of PKC on vascular KNDP and cardiac KATP activity. Moreover, the lack of effect of PKC on LK channels of rat PV indicates that they likely possess a subunit composition distinct from that of KNDP and cardiac KATP.
We favor the view that the KNDP channels are directly regulated by PKC-dependent phosphorylation of the Kir6.x or SUR subunit(s). The ability of PKM to cause a rapid inhibition of channel activity in I-O membrane patches in this study is consistent with this interpretation. However, angiotensin II also activates signaling cascades involving mitogen-activated protein kinase and tyrosine kinase, and inhibitors of tyrosine kinase activity were previously found to block the reduction in esophageal smooth muscle KATP current by M3 receptor activation or phorbol esters.34 Angiotensin II inhibited arterial KATP currents via PKC,20 but whether tyrosine kinase also regulates vascular KNDP remains to be determined. Further characterization of the signaling pathways for regulation of KNDP, identification of the PKC isoform(s) involved, and determination of the molecular mechanism(s) involved will require the use of purified PKC isoenzymes, isoform-specific antibodies, and identification of the specific phosphorylation sites within the KNDP channels.
In summary, these results provide the first evidence that a decline in KNDP channel activity may contribute to the previously reported inhibition of whole-cell KATP currents by activators of PKC.35 36 37 Reduction in the open probability of the KNDP subtype of vascular KATP channel due to an increased occupancy of a long-duration interburst closed state may contribute to depolarization, Ca2+ channel activation, and increased vascular smooth muscle tone in response to vasoconstrictors that activate PKC.
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Acknowledgments |
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This work was supported by Heart and Stroke Foundation of Alberta, Northwest Territory and Nunavut. W.C.C. is a Senior Scholar and M.P.W. is a Medical Scientist of the Alberta Heritage Foundation for Medical Research.
Received May 1, 2000; accepted June 13, 2000.
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