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Am J Physiol Heart Circ Physiol 291: H2541-H2546, 2006. First published July 28, 2006; doi:10.1152/ajpheart.00420.2006
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Signaling pathway underlying stimulation of L-type Ca2+ channels in rabbit portal vein myocytes by recombinant Gbeta{gamma} subunits

Brid Callaghan,1 Juming Zhong,2 and Kathleen D. Keef1

1Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, Nevada; and 2Department of Anatomy, Physiology, and Pharmacology, Auburn University College of Veterinary Medicine, Auburn, Alabama

Submitted 26 April 2006 ; accepted in final form 20 July 2006


   ABSTRACT
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 ABSTRACT
METHODS
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 DISCUSSION
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In previous studies, we (Callaghan B, Koh SD, and Keef KD, Circ Res 94: 626–633, 2004) have shown that voltage-dependent L-type Ca2+ channels (Cav) in portal vein myocytes are enhanced when muscarinic M2 receptors are activated with ACh. Current stimulation was coupled to the G protein subunit Gbeta{gamma} along with the downstream mediators phosphatidylinositol-3-kinase (PI3K), protein kinase C (PKC), and c-Src. The present study was designed to determine whether the same second messenger pathway could be identified when exogenous recombinant Gbeta{gamma} subunits are introduced into cells. Smooth muscle myocytes were freshly isolated from rabbit portal vein, and Cav currents were recorded by using the patch-clamp technique. Dialysis of cells with recombinant Gbeta{gamma} (50 nM) significantly increased Cav currents (141%). Nifedipine (1 µM) reduced both control and stimulated currents by ~90%. The enhancement of current by Gbeta{gamma} was equivalent to that produced by ACh (142%), whereas the PKC activator phorbol 12,13-dibutyrate (PdBu) gave rise to greater current stimulation (192%). Current stimulation with Gbeta{gamma}, ACh, and PdBu were not associated with changes in the voltage dependence of activation or inactivation. The PI3K inhibitor LY-294002 (20 µM) reduced peak currents by 32% in cells dialyzed with Gbeta{gamma}, whereas the inactive analog LY-303511 resulted in a small but significant reduction in current (12%). The c-Src inhibitor PP2 (1 µM) also significantly reduced currents (34%), whereas the inactive analog PP3 was without effect. These data provide further evidence for the hypothesis that Gbeta{gamma} leads to stimulation of Cav currents in rabbit portal vein myocytes via a signaling pathway that includes PI3K, PKC, and c-Src.

vascular calcium channel; G protein beta{gamma} subunits; tyrosine kinase

THE ACTIVITY of voltage-dependent L-type Ca2+ channels (Cav) can be modified by a number of hormones and mediators coupled to G protein-coupled receptors (GPCR) (1, 12, 27). G proteins are heterotrimers consisting of G{alpha} and Gbeta{gamma} subunits. Receptor activation of G proteins causes GDP replacement with GTP and separation of G{alpha} and Gbeta{gamma} subunits, which can target different effectors (20). In previous studies, we and others have shown that endogenous Gbeta{gamma} coupled to either Gi, Gs, or G13, as well as exogenous Gbeta{gamma} dialyzed into cells, leads to stimulation of Cav currents in portal vein myocytes (6, 18, 37, 42, 43).

Gbeta{gamma} has been shown to activate some isoforms of phosphatidylinositol-3-kinase (PI3K; Ref. 4), and substantial evidence has accumulated to suggest that Gbeta{gamma} stimulation of Cav in portal vein is coupled to activation of PI3K{gamma} (6, 26). We and others have also proposed that a downstream mediator of PI3K after muscarinic M2 receptor activation of Gbeta{gamma} is PKC (6, 39), which in turn can give rise to activation of c-Src (6). c-Src also appears to mediate stimulation of Cav currents with M2 receptors stimulation in rabbit colonic myocytes (13), integrin {alpha}5beta1-mediated stimulation of Cav currents in cremaster arteriolar myocytes (41), and PDGF receptor stimulation in rabbit ear artery (40). In the present study, we have further investigated the Gbeta{gamma}/PI3K/PKC/c-Src pathway by evaluating whether PI3K and c-Src are necessary for stimulation of Cav currents when exogenous recombinant Gbeta{gamma} is dialyzed into portal vein myocytes.


   METHODS
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 METHODS
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Isolation of Rabbit Portal Vein Myocytes

Male albino rabbits (1.5–2 kg; Western Oregon Rabbitry, Philomath, OR) were killed with an intravenous overdose of Euthasol. The protocol was reviewed and approved by the Animal Care and Use Committee of the University of Nevada. The portal vein was removed from the rabbit, and myocytes were isolated by using previously described methods (42).

Electrophysiology

Patch-clamp experiments were performed as previously described (43). Inward currents were measured by using an Axopatch-1D patch-clamp amplifier, digitized with a 16-bit analog-to-digital converter (model DIGIDATA 1320A, Axon Instruments), and controlled by pClamp8 (Axon Instruments). Cav currents in myocytes were measured by using either the dialyzed or perforated whole cell patch configuration. The bath solution used to record Cav current was composed of (in mmol/l) 115 NaCl, 10 TEACl, 10 BaCl2, 0.5 MgCl2, 5.5 glucose, 5 CsCl, and 10 HEPES, adjusted to pH 7.40 with NaOH. Both TEACl and CsCl were used to block potassium currents. The pipette solution used for the dialyzed whole cell experiment was composed of (in mmol/l) 120 CsCl, 20 TEACl, 5.5 glucose, 2 MgCl2, 5 ATP, 5 EGTA, and 10 HEPES, adjusted to pH 7.2 with CsOH. The pipette solution used for the perforated patch experiments was composed of (mmol/l) 120 cesium aspartate, 20 TEACl, 1 EGTA, and 20 HEPES, adjusted to pH 7.2 with CsOH. Amphotericin B (90 mg/ml) was dissolved with DMSO, sonicated, and diluted to give a final concentration of 270 µg/ml in the pipette solution.

Determination of the voltage dependence of activation and inactivation. Activation relationships were determined by calculating the peak conductance at each test potential by using the equation ICa = gCa x (V – Erev), where gCa, V, and Erev are peak conductance, test potential, and reversal potential, respectively, and ICa is calcium channel current. A double-pulse protocol was used to measure inactivation of Cav current as a function of membrane potential. Conditioning steps from –70 to +40 mV were applied for 540 ms. After a 3-ms step to –70 mV, the membrane potential was stepped to 0 mV for 350 ms. Resulting currents were normalized to the maximum current obtained after a conditioning potential of –70 mV (I/Imax) and plotted as a function of the conditioning potential. The data were fitted by a Boltzmann equation.

Drugs

Collagenase type I, protease type XXVII, phorbol 12,13-dibutyrate (PdBu), ACh, nifedipine, and BSA were purchased from Sigma. 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), the inactive analog PP3, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY-294002), the inactive analog LY-303511, and recombinant Gbeta1human{gamma}2bovine were purchased from Calbiochem.

Data Analysis

All experimental values are presented as means ± SE, and n refers to the number of cells tested. Differences between the values from different groups were compared by using Student’s paired and unpaired t-test and two-way ANOVA, where appropriate. P < 0.05 was considered significantly different.


   RESULTS
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Comparison of Current Stimulation with Recombinant Gbeta{gamma}, ACh, and PdBu

To study the effects of Gbeta{gamma} on Cav currents, we used the conventional whole cell technique, and Gbeta{gamma} (50 nM) was dialyzed into the cells by including it in the patch pipette solution. Currents recorded from these cells were compared with control cells lacking Gbeta{gamma}. Cells dialyzed with Gbeta{gamma} generated peak Cav currents, which were significantly greater than control currents (Figs. 1 and 2A). Nifedipine (1 µM) abolished the difference in current amplitude between control cells and cells dialyzed with Gbeta{gamma}. The current remaining in the presence of nifedipine was ~10% of the former peak current amplitude. These data suggest that both control currents and Gbeta{gamma}-stimulated currents were due to L-type calcium channels (Fig. 1).


Figure 1
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  		Fig. 1. Control currents and currents recorded in the presence of Gbeta{gamma} are blocked by nifedipine (Nif; 1 µM). Top: sample traces of control currents (left) and currents obtained in cells dialyzed with 50 nM Gbeta{gamma} (right). In both cases, currents were greatly diminished by exposure to nifedipine. Bottom: plot of the current-voltage (I-V) relationship for voltage-dependent L-type Ca2+ channel (Cav) currents under control conditions ({blacksquare}) and in the presence of Gbeta{gamma} ({circ}). At a step potential to 0 mV, currents with nifedipine ({lozenge}; *) were ~10% of the former maximum. I-V curves in the presence of nifedipine are not different from one another but are significantly less than those recorded in the absence of nifedipine (P < 0.05). Values are means ± SE.

 

Figure 2
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  		Fig. 2. Gbeta{gamma}, ACh, and phorbol 12,13-dibutyrate (PdBu) enhance Cav currents in rabbit portal vein myocytes. A: bar graph summarizing the effects of Gbeta{gamma} (50 nM, n = 42), ACh (10 µM, n = 21), and PdBu (100 nM, n = 19) on peak Cav currents recorded during a voltage step to 0 mV. Bars labeled "C" indicate control currents associated with each experimental protocol. Gbeta{gamma}, ACh, and PdBu all gave rise to significantly greater (*P < 0.05) peak currents. Activation (B, D, and F) and inactivation relationships (D, E, and G) obtained for these experiments are shown. The voltage protocols for activation and inactivation are shown in D, inset, and E, inset, respectively. Neither Gbeta{gamma} (n = 6 Gbeta{gamma}, n = 4 control), ACh (n = 16 ACh, n = 15 control), nor PdBu (n = 11 PdBu, n = 11 control) led to a significant shift in either the activation or the inactivation relationship. Values are means ± SE.

 
We have shown that ACh enhances Cav currents in portal vein myocytes via M2 receptors coupled to Gi and that a downstream second messenger of the Gbeta{gamma} pathway is PKC (6). For this reason, the stimulatory effects of Gbeta{gamma} were compared with those of ACh and the PKC activator PdBu. Responses to ACh and PdBu were recorded by using the perforated whole cell mode, and currents were measured before and after bath application of either ACh (10 µM) or PdBu (100 nM). ACh gave rise to the same percent current stimulation as that observed with Gbeta{gamma} (i.e., 142 ± 5% vs. 141 ± 2% of control, respectively), whereas PdBu induced significantly greater stimulation (192 ± 4% of control) (Fig. 2A). The voltage dependence of activation and inactivation for Gbeta{gamma}, ACh, and PdBu was also determined. Neither Gbeta{gamma}, ACh, nor PdBu significantly shifted the voltage dependence of activation or inactivation (Fig. 2, B–G).

Effect of PI3K and c-Src Blockers on Gbeta{gamma} Stimulation of Cav

To determine the possible involvement of PI3K in the stimulation of Cav currents by exogenous Gbeta{gamma}, we tested the PI3K inhibitor LY-294002 (20 µM) and compared it with the inactive analog LY-303511 (20 µM). LY-294002 or LY-303511 was applied after development of a steady-state current in cells dialyzed with Gbeta{gamma}. LY-294002 significantly reduced currents by 32.5 ± 4.5% (n = 13), whereas a smaller but significant reduction (12 ± 2.5%, n = 11) was observed with LY-303511 (Fig. 3). In contrast, LY-294002 did not significantly affect currents in control cells (n = 5). These data are in agreement with a previous study in which Gbeta{gamma}-induced stimulation of Cav in rat portal vein myocytes was blocked by the PI3K inhibitor wortmannin (38).


Figure 3
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  		Fig. 3. Stimulation of Cav by Gbeta{gamma} is dependent on phosphatidylinositol-3-kinase (PI3K). Sample current traces (A and D), as well as the time courses for these effects (B and E), are shown for the inactive analog LY-303511 (LY30) (A–C) and for the active PI3K inhibitor LY-294002 (LY29; D–F). Examples of currents before (1) and during (2) drug addition are shown in A and D and labeled in B and E. Both LY-303511 (C, n = 11) and LY-294002 (F, n = 13) significantly reduced peak Cav currents (*P < 0.05, paired t-test), although the inhibition with LY-294002 was significantly greater than that observed with LY-303511 (#P < 0.05, nonpaired t-test). Values are means ± SE.

 
A final group of experiments was performed to determine the possible involvement of c-Src in the actions of exogenous Gbeta{gamma}. To do this, we compared the effects of the c-Src inhibitor PP2 (1 µM) with those of the inactive analog PP3. PP3 or PP2 was applied after development of a steady-state current in cells dialyzed with Gbeta{gamma}. PP2 significantly reduced currents by 33.8 ± 3.73% (n = 8), whereas PP3 (n = 5) was without effect (Fig. 4). Addition of PP2 to control cells did not significantly affect currents (n = 5).


Figure 4
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  		Fig. 4. Stimulation of Cav by Gbeta{gamma} is dependent on c-Src. Sample current traces (A and D), as well as the time courses for these effects (B and E), are shown for the inactive analog PP3 (A–C) and for the active c-Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) (D–F). Examples of currents before (1) and during (2) drug addition are shown in A and D and labeled in B and E. Whereas PP3 (C; n = 5) was without effect on Cav currents, PP2 (F; n = 8) significantly reduced peak Cav currents (*P < 0.05, paired t-test). Values are means ± SE.

 

   DISCUSSION
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GRANTS
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G protein beta{gamma} subunits modulate various ion channels via different signaling pathways. For example, Gbeta{gamma} inhibits N- and P/Q-type Ca2+ channels by the direct binding of beta{gamma} dimers to the {alpha}1-interaction domain of these Ca2+ channels (9, 11). Gbeta{gamma} subunits can also activate K+ channels in cardiac cells by both direct and indirect pathways (30). In the present study, Cav currents were significantly greater in cells dialyzed with Gbeta{gamma}. The stimulatory effect of Gbeta{gamma} on Cav currents was the same as that produced by ACh (which activates endogenous Gbeta{gamma} via M2 receptors coupled to Gi) but smaller than that of PdBu. In previous studies, we have shown that the actions of ACh and Gbeta{gamma} on Cav currents involve specifically a novel PKC (6, 42). In contrast, PdBu activates both classical and novel PKCs, and both of these classes of PKC can enhance Cav currents (6, 10, 15, 19, 22, 29, 36). It is therefore possible that the greater effect of PdBu on Cav currents observed in this study is due to the involvement of multiple PKC-dependent pathways. Despite this difference, in each case current stimulation was independent of a change in the voltage dependence of either activation or inactivation of Cav currents. Other possible mechanisms that could account for current stimulation might be an increase in channel open times (21, 33) or an increase in translocation of channels to the plasma membrane (35).

There is substantial evidence linking Gbeta{gamma} to the activation of PI3K (4). Furthermore, the present study, as well as previous work by our group and others, suggests that Gbeta{gamma} stimulation of Cav in portal vein myocytes is linked to activation of PI3K (6, 17, 26, 36). We have also suggested that PKC is involved in this pathway because stimulation of Cav currents in portal vein myocytes after either dialysis of cells with recombinant Gbeta{gamma} (42) or activation of endogenous Gbeta{gamma} via either M2 receptors (6) or beta-adrenergic receptors (43) is blocked with antagonists of PKC. Dialysis of Gbeta{gamma} purified from rat brain Gi has also been reported to stimulate Cav currents in rat portal vein via a pathway involving PI3K and PKC (36). An important lipid product of PI3K is the polyphosphoinositide, phosphatidylinositol 3,4,5-trisphosphate (PIP3) (34), and PIP3 is known to recruit 3'-phosphoinositide-dependent kinase (PDK-1) to the plasma membrane (32). PDK-1 can activate novel and atypical PKCs in the presence of PIP3 by phosphorylation of the PKC activation loop (7, 14, 24, 31). Thus the functional studies discussed here suggest a role for both PI3K and PKC in the Gbeta{gamma} pathway, and this is supported by biochemical evidence linking PI3K to PKC.

In portal vein myocytes, we previously reported that a novel PKC in particular participates in the Gbeta{gamma} pathway and that downstream of this novel PKC is c-Src (6, 42). c-Src is abundant in vascular smooth muscle (23), and a number of studies have suggested that PKC can enhance c-Src activity (5, 8, 16, 25, 28). The present study provides additional support for a role for c-Src in the Gbeta{gamma} pathway by showing that the action of recombinant Gbeta{gamma} is reversed by the c-Src inhibitor PP2. Recent studies have specifically linked novel PKC{delta} to c-Src stimulation (2). PKC{delta} activates c-Src by stimulating the protein tyrosine phosphatase, PTP{alpha}. PTP{alpha} dephosphorylates a c-terminal tyrosine on c-Src, leading to unfolding of c-Src, autophosphorylation of the catalytic domain, and activation of the kinase (3). Thus the functional studies described here suggest a role for both PKC and c-Src in the Gbeta{gamma} pathway, and this is supported by biochemical studies showing a link between PKC and c-Src.

In summary, the present study further investigates the pathway by which Gbeta{gamma} gives rise to Cav current stimulation in portal vein myocytes by dialyzing cells with exogenous recombinant Gbeta{gamma} subunits. Our results suggest that exogenous Gbeta{gamma} stimulates Cav currents via a similar pathway to that evoked by endogenous Gbeta{gamma} and that PI3K, PKC, and c-Src are all downstream second messengers in this pathway.


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This work was supported by National Heart, Lung, and Blood Institute Grant RO1-HL-40399 to K. D. Keef.


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. D. Keef, Dept. of Physiology and Cell Biology, Univ. of Nevada, School of Medicine, Reno, NV 89573 (e-mail: kkeef{at}unr.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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00420.2006v1
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