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. 2000 Aug 15;527(Pt 1):3–9. doi: 10.1111/j.1469-7793.2000.t01-2-00003.x

Laminin binding to β1-integrins selectively alters β1- and β2-adrenoceptor signalling in cat atrial myocytes

Yong Gao Wang 1, Allen M Samarel 1, Stephen L Lipsius 1
PMCID: PMC2270063  PMID: 10944166

Abstract

  1. Perforated patch recordings were used to determine how plating atrial cells on laminin alters β-adrenergic receptor (β-AR) regulation of L-type Ca2+ current (ICa,L).

  2. Isoproterenol (isoprenaline; ISO; 0.01 μM), a non-selective β-AR agonist, elicited a greater stimulation of ICa,L in cells plated on laminin (+79 ± 16%; n = 17) than on glass (+33 ± 5%; n = 23). Also, desensitization to ISO was greater in cells on laminin (−16 ± 2%) than on glass (−3 ± 1%). Atenolol (0.1 μM), a selective β1-AR antagonist, inhibited the effects of ISO in cells on glass but not laminin. Conversely, 0.1 μM ICI 118,551, a selective β2-AR antagonist, inhibited the effects of ISO in cells on laminin but not glass. With β2-ARs blocked, ISO-induced stimulation of ICa,L was greater in cells on glass than laminin.

  3. Zinterol (0.01–0.1 μM), a selective β2-AR agonist, elicited a greater stimulation of ICa,L in cells on laminin than on glass. The effects of zinterol were blocked by ICI 118,551.

  4. ISO-induced stimulation of ICa,L was greater in cells plated on an αβ1-integrin antibody than on glass. Also, addition of 20 μM cytochalasin D to cells on laminin prevented the enhanced effects of ISO typically elicited in cells on laminin alone.

  5. We conclude that laminin binding to αβ1-integrins, in conjunction with the actin cytoskeleton, reduces β1-AR and enhances β2-AR signalling which regulates ICa,L. This novel mechanism may contribute to remodelling of β-AR signalling in the failing heart.

Cardiac muscle contains both β1- and β2-adrenergic receptor (AR) signalling mechanisms (Steinberg, 1999). In general, the density of β2-ARs is lower than that of β1-ARs (Steinberg, 1999), and higher in atrial than ventricular muscle (Stiles et al. 1983). β2-ARs are more efficiently coupled to Gs-protein/adenylate cyclase (AC) than are β1-ARs (Green et al. 1992; Levy et al. 1993), resulting in a greater sensitivity to β2-AR agonist stimulation. In addition, within seconds of agonist exposure β2-ARs exhibit desensitization resulting from phosphorylation by β-AR kinases (Muntz et al. 1994). β-AR signalling is especially important in the failing heart, which exhibits dramatic and selective remodelling of β1- and β2-AR signalling (Xiao et al. 1999b). However, the mechanisms responsible for remodelling of β-adrenoceptor signalling are not clear.

Laminin is one component of the cardiac extracellular matrix (ECM), whose content and composition undergo profound alterations in response to pathological conditions. Cardiomyocytes attach to laminin and other ECM components via low-affinity, cell surface receptors known as integrins. Integrins comprise a family of heterodimeric transmembrane proteins consisting of various alpha (α) and beta (β) chains which combine to give the integrin complex several different ECM-binding specificities. Adult cardiac myocytes readily attach to laminin via β1-integrin receptors (Terracio et al. 1991). Integrins transduce biochemical and mechanical stimuli into the cell to regulate various cellular functions (Cary et al. 1999). Our previous work indicates that laminin binding to β1-integrins alters cholinergic regulation of ICa,L by depressing AC activity (Wang et al. 2000). In the present study we report that attachment of atrial myocytes to laminin selectively reduces β1- and enhances β2-AR signalling mechanisms which regulate ICa,L. These findings may be relevant to the mechanisms underlying β-AR remodelling in the failing heart.

METHODS

Adult mongrel cats of either sex were anaesthetized with sodium pentobarbital (70 mg kg−1i.p.). After bilateral thoracotomy, the heart was rapidly excised and mounted on a Langendorff perfusion apparatus for cell isolation, as described (Wu et al. 1991). Experiments were performed on quiescent atrial cells, without discernable differences in response between right or left atria. Cells were plated on substrates according to methods reported (Wang et al. 2000). Substrates included: laminin (20 μg ml−1), poly-L-lysine (20 μg ml−1), goat anti-human αβ1-integrin IgG (20 μg ml−1) (antibody generously provided by Dr T. K. Borg, University of South Carolina Medical School, Charleston, SC, USA) or goat non-immune IgG (20 μg ml−1) (Chemicon). Cells were plated on each substrate for at least 2 h before recordings were performed. Attachment of cardiac myocytes to laminin requires about 30–60 min (Berlin, 1995). Cells plated on glass alone for 1–6 h exhibited similar responses to isoproterenol. Coverslips containing cells were transferred to a tissue bath (0.3 ml) on the stage of an inverted microscope and superfused (∼5 ml min−1) with a Tyrode solution (35 ± 1°C) containing (mM): NaCl 137, KCl 5.4, MgCl2 1.0, CaCl2 2.0, Hepes 5, glucose 11, and was titrated with NaOH to pH 7.4. Ionic currents were recorded in the discontinuous mode using an Axoclamp 2A amplifier (Axon Instruments, Inc.) and a nystatin (150 μg ml−1)-perforated patch whole-cell recording method. Internal pipette solution contained (mM): caesium glutamate 100, CsCl 40, MgCl2 1.0, Na2-ATP 4, EGTA 0.5, Hepes 5, and was titrated with CsOH to pH 7.2. To block K+ current, Cs+ replaced K+ in the internal pipette solution and 5 mM CsCl was added to all external solutions. ICa,L was activated by clamp steps from a holding potential of −40 mV to 0 mV for 200 ms every 5 s. Peak ICa,L was measured with respect to steady-state current, without compensation for leak currents. Inward currents are verapamil-sensitive L-type Ca2+ currents (Wang & Lipsius, 1995). Desensitization was measured as the percentage change between maximum and steady-state peak ICa,L. In any given experiment, cells plated on different substrates and tested with agonist were obtained from the same heart. Drugs included: isoproterenol (ISO) (Sigma), zinterol (provided by Bristol-Myers Squibb, Princeton, NJ, USA), atenolol (Sigma), ICI 118,551 (provided by AstraZeneca, Wilmington, DE, USA), cytochalasin D (Sigma). Atenolol, ICI 118,551, cytochalasin D or integrin antibody alone exerted no significant effects on basal ICa,L.

Data are expressed as means ±s.e.m. Mean agonist responses were expressed as mean percentage change above control for each cell. Data from two groups of cells were analysed using Student's unpaired two-tailed t test with significance accepted at P < 0.05. Data from among three groups of cells were analysed using a one-way analysis of variance (ANOVA) followed by Student-Newman-Keuls test at P < 0.05.

Experimental and animal procedures used were in accordance with guidelines of the Animal Care and Use Committee of Loyola University Medical Center.

RESULTS

Basal Ca2+ current density is about 20% smaller in cells plated on laminin than on glass (Wang et al. 2000). Figure 1 shows typical effects of 0.01 μM ISO, a non-selective β-AR agonist, on ICa,L recorded from atrial myocytes plated on glass (Fig. 1A–D) or laminin (Fig. 1E–H) in the absence and presence of antagonists for β1-ARs (atenolol) or β2-ARs (ICI 118,551). In the absence of antagonists, ISO-induced stimulation of ICa,L was greater in a cell on laminin (+202%) (Fig. 1E and F) than in a cell on glass (+25%) (Fig. 1A and B). In total, ISO increased ICa,L in cells on laminin (+79 ± 16%; n = 17) significantly more than on glass (+33 ± 5%; n = 23) (P < 0.005). These values represent the peak effects of ISO at about 1 min of exposure. With continued exposure to ISO, ICa,L amplitude decreased over time, i.e. desensitized, significantly more in cells on laminin (−16 ± 2%; n = 17) (Fig. 1E and F) than in cells on glass (−3 ± 1%; n = 23; P < 0.001) (Fig. 1A and B). Steady-state current-voltage (I-V) relationships showed that ISO-induced stimulation of ICa,L was enhanced in cells on laminin compared with glass at test voltages between −20 and +40 mV (data not shown). Also, the effect of ISO of stimulating ICa,L more in cells on laminin than on glass was not related to baseline ICa,L amplitude. These findings indicate that laminin enhances the maximum response and desensitization to β-AR stimulation, both characteristics of β2-AR signalling.

Figure 1. Effects of ISO (0.01 μM) on ICa,L in atrial myocytes plated on glass and laminin in the absence and presence of atenolol or ICI 118,551.

Figure 1

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Myocytes were plated on glass (A-D) and laminin (E-H) in the absence (A and B; E and F) and presence of 0.1 μM atenolol (C and G) or 0.1 μM ICI 118,551 (ICI) (D and H). A and E, original traces of ICa,L obtained during the labelled points (a, b, c) shown in panels B and F. B-D and F-H, consecutive measurements of peak ICa,L recorded from six different atrial myocytes. In the absence of antagonists, ISO-induced stimulation of ICa,L and desensitization were greater in a cell on laminin (E and F) than in a cell on glass (A and B). In the presence of atenolol, ISO-induced stimulation of ICa,L and desensitization were greater in a cell on laminin (G) than in one on glass (C). In the presence of ICI, ISO stimulated ICa,L to a greater extent in a cell on glass (D) than in one on laminin (H) and neither exhibited desensitization. Data obtained from a total of eight hearts.

To assess the role of β2-AR signalling, 0.01 μM ISO was tested in the presence of 0.1 μM atenolol, a selective β1-AR antagonist, in cells on glass (Fig. 1C) and laminin (Fig. 1G). On glass, ISO-induced stimulation of ICa,L was almost completely blocked (+11%). However, on laminin ISO elicited a prominent stimulation of ICa,L (+47%) that also exhibited desensitization. In total, in the presence of atenolol, ISO-induced stimulation of ICa,L was greater in cells on laminin (+102 ± 26%; n = 8) than on glass (+13 ± 4%; n = 7) (P < 0.01). Also, desensitization in cells plated on laminin (−12 ± 4%) was significantly greater than that in cells on glass (+3 ± 3%) (P < 0.05). These findings suggest that plating atrial cells on laminin enhances β2-AR signalling.

To determine whether laminin alters β1-AR signalling, 0.01 μM ISO was tested in the presence of 0.1 μM ICI 118,551 (ICI), a selective β2-AR antagonist (O'Donnell & Wanstall, 1980). As shown in Fig. 1D and H, ICI inhibited ISO-induced stimulation of ICa,L in a cell on laminin (Fig. 1H) (+14%) but not on glass (Fig. 1D) (+61%). Moreover, desensitization did not occur in either glass- (Fig. 1D) or laminin-plated (Fig. 1H) cells. In total, ISO-induced stimulation of ICa,L was greater in cells on glass (+51 ± 16%; n = 6) than on laminin (+12 ± 6%; n = 9) (P < 0.05) and neither group exhibited desensitization. These findings indicate that laminin-binding also decreases β1-AR signalling.

The combined presence of β1-AR (0.1 μM atenolol) and β2-AR (0.1 μM ICI 118,511) antagonists abolished ISO-induced stimulation of ICa,L in cells plated on either glass (+5 ± 5%; n = 3) or laminin (+2 ± 6%; n = 3). In addition, cells plated on poly-L-lysine (20 μg ml−1; ≥ 2 h), a non-specific substrate for cell attachment, failed to exhibit enhanced stimulation of ICa,L by ISO (+96 ± 32%; n = 7) compared with cells on glass (+132 ± 47%; n = 7), and neither cells on poly-L-lysine nor glass exhibited significant desensitization.

Our interpretation that laminin enhances β2-AR signalling was examined further by determining the effects of zinterol, a specific β2-AR agonist. Zinterol was administered in the presence of 0.2 μM atenolol to ensure β2-AR stimulation. As shown in Fig. 2, in a cell on glass (Fig. 2A), 0.1 μM zinterol induced stimulation of ICa,L (+85%) with little desensitization. In a cell on laminin (Fig. 2B), zinterol induced prominent stimulation of ICa,L (+461%) and desensitization. As summarized in Fig. 2C, 0.1 μM zinterol-induced stimulation of ICa,L was greater in cells on laminin (+459 ± 55%; n = 7) than on glass (+122 ± 28%; n = 7) (P < 0.01). Qualitatively similar results were obtained with 0.01 μM zinterol (plus atenolol) in cells on laminin (+162 ± 28%; n = 11) versus glass (+23 ± 4%; n = 8) (P < 0.05). Desensitization was significantly greater in cells on laminin (−8 ± 2%) than on glass (−0.4 ± 0.6%) (P < 0.05). These findings indicate that β2-AR signalling is normally present in atrial myocytes and is enhanced in cells on laminin. The addition of 0.1 μM ICI 118,511 abolished 0.1 μM zinterol (plus atenolol)-induced stimulation of ICa,L in cells plated on glass (+5%; n = 2) or laminin (+2%; n = 2).

Figure 2. Effect of 0.1 μM zinterol on ICa,L in atrial myocytes plated on glass (A) and laminin (B).

Figure 2

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A and B, consecutive measurements of peak ICa,L and selected original traces of ICa,L (insets) obtained at the times indicated (a, b). Zinterol-induced stimulation of ICa,L and desensitization were greater in a cell on laminin (B) than in one on glass (A). C, effects of 0.01 and 0.1 μM zinterol on ICa,L in cells on glass (GLS; □) and laminin (LAM;Inline graphic). Numbers in parentheses are numbers of cells studied. Data obtained from a total of four hearts.

The role of β1-integrins was evaluated by plating atrial myocytes on glass or goat anti-human αβ1-integrin polyclonal IgG (20 μg ml−1), an antibody raised against αβ1-integrin receptors. As shown in Fig. 3, in a cell on glass (Fig. 3A) ISO (0.01 μM) stimulated ICa,L (+25%) without desensitization. In contrast, on αβ1-IgG (Fig. 3B) ISO-induced stimulation of ICa,L (+117%) and desensitization were enhanced. As summarized in Fig. 3C, ISO-induced stimulation of ICa,L was significantly greater in cells on αβ1-IgG (+91 ± 17%; n = 8) than on glass (+26 ± 7%; n = 5) (P < 0.01). In addition, desensitization in cells on αβ1-IgG and glass was −12 ± 4 vs.−2 ± 1%, respectively. As a control, ISO-induced stimulation of ICa,L was not different in cells plated on glass (+72 ± 9%; n = 3) or a non-immune goat IgG (+60 ± 19%; n = 3), and neither group exhibited desensitization. That the αβ1-integrin antibody mimicked the effects of laminin suggests that laminin alters β-AR signalling via binding to αβ1-integrins.

Figure 3. Effect of 0.01 μM ISO on ICa,L in atrial myocytes plated on glass (A) and αβ1-IgG (B).

Figure 3

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A and B, consecutive measurements of ICa,L. ISO-induced stimulation of ICa,L and desensitization were greater in a cell on αβ1-IgG (B) than in one on glass (A). C, ISO-induced stimulation of ICa,L was significantly greater in cells on αβ1-IgG (Inline graphic) than on glass (GLS; □). Data obtained from a total of two hearts.

Integrins act via changes in the actin cytoskeleton (Defilippi et al. 1999). In Fig. 4A–C, ISO (0.01 μM) was tested in cells plated on glass (+25%; Fig. 4A), laminin (+59%; Fig. 4B) or laminin + 20 μM cytochalasin D (Cyto D) (+21%; Fig. 4C), an agent that prevents actin polymerization. Cyto D prevented the enhanced stimulation of ICa,L and desensitization typically induced by ISO in laminin-plated cells. As summarized in Fig. 4D, ISO-induced stimulation of ICa,L was similar in cells on glass (+30 ± 5%; n = 7) and laminin + Cyto D (+31 ± 5%; n = 9) and significantly larger than either on laminin alone (+61 ± 10%; n = 9) (P < 0.05). Moreover, desensitization was not different in cells on laminin + Cyto D (−5 ± 1%) compared with glass (−2 ± 1%) but significantly larger than either on laminin alone (−16 ± 2%) (P < 0.05). These findings suggest that the actin cytoskeleton plays an essential role in the laminin-mediated switching of β-AR signalling mechanisms. These findings are consistent with our previous work showing that laminin acts via αβ1-integrins and the actin cytoskeleton to alter cholinergic regulation of ICa,L (Wang et al. 2000).

Figure 4. Effects of 0.01 μM ISO on ICa,L in cells plated on glass (A), laminin (B) and laminin plus 20 μM cytochalasin D (Cyto D) (C).

Figure 4

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A-C, ISO stimulated ICa,L to a similar extent, without desensitization, in a cell on glass (A) and one on laminin + Cyto D (C), and to a larger extent, with desensitization, in a cell on laminin alone (B). D, ISO-induced stimulation of ICa,L was similar in cells plated on glass (GLS; □) and laminin (LAM) + Cyto D (Inline graphic), and greater than either in cells on LAM alone (Inline graphic). Data obtained from a total of four hearts.

DISCUSSION

The present results indicate that cat atrial myocytes exhibit both β1-AR and β2-AR signalling mechanisms that regulate ICa,L. Cells plated on glass exhibit predominately β1-AR signalling, similar to human right atrial tissue (Brodde et al. 1983). However, plating cells on laminin selectively reduces β1-AR signalling and enhances β2-AR signalling. These effects of laminin are mediated via αβ1-integrin receptors in conjunction with the actin cytoskeleton. We believe this is the first report to demonstrate that the laminin-integrin- cytoskeletal complex can selectively alter β-AR signalling mechanisms that regulate ICa,L in cardiac myocytes.

Our previous work indicates that in atrial myocytes basal ICa,L, basal cAMP and forskolin-stimulated cAMP levels are significantly smaller in cells plated on laminin than on glass (Wang et al. 2000). However, stimulation of ICa,L, elicited by 8-CPT-cAMP, a membrane-permeant analogue of cAMP, or intracellular dialysis of cAMP, was not significantly different between cells plated on glass or laminin. In relation to the present study, these findings suggest that the effects of laminin of altering β-AR signalling are not due to changes in the cAMP signalling pathway that are distal to the synthesis of cAMP. This would include mechanisms such as cAMP-dependent protein kinase A, phosphodiesterases or phosphatases, or changes in the sensitivity of L-type Ca2+ channels to cAMP. The effects of laminin, therefore, must be proximal to cAMP. In fact, our previous study indicates that laminin acts via αβ1-integrins and the actin cytoskeleton to depress AC activity (Wang et al. 2000). This may contribute, at least in part, to the laminin-mediated selective reduction in β1-AR signalling reported here. However, depressed AC activity appears inconsistent with the enhanced β2-AR response elicited in cells on laminin. Several possible mechanisms could account for this apparent disparity. First, the more efficient coupling of β2-ARs to Gs/AC (Green et al. 1992; Levy et al. 1993) may overcome, to some extent, the laminin-mediated depression in AC. Furthermore, atrial muscle exhibits at least three different isoforms of AC: types V and VI and, specific to atrial muscle, type III (Ishikawa & Homcy, 1997). β1-ARs and β2-ARs may be preferentially coupled to different AC isoforms that are affected differently by integrin engagement. Moreover, different AC isoforms are regulated differently by specific G-protein subunits (Taussig et al. 1994; Ishikawa & Homcy, 1997). Also, β2-AR signalling may act via a cAMP-independent mechanism (Steinberg, 1999).

Although the intracellular signalling events responsible for enhanced β2-AR signalling following integrin engagement by laminin are not known, there are several possibilities. Integrin engagement could alter β2-AR coupling to G-proteins. In ventricular myocytes β2-ARs can couple to both Gs- and Gi-proteins (Xiao et al. 1999a,b), although this dual G-protein coupling to β2-ARs may not occur in atrial muscle (Kaumann et al. 1996). In addition, coupling of β2-ARs to G-proteins depends on conformational changes in receptor structure (for review see Hein & Kobilka, 1995), which could be affected by alterations in cytoskeletal architecture. Integrin-mediated alterations in cell signalling can be exerted through structural changes via the actin-based cytoskeleton, and/or via activation of cell signalling cascades involving protein phosphorylation. For example, integrin engagement and clustering induces the autophosphorylation of focal adhesion kinase, which can rapidly initiate signalling cascades involving other protein tyrosine kinases, phosphatidylinositol-3 (PI-3) kinase, and extracellular signal-regulated kinase 1/2 (ERK1/2) signalling (see Schlaepfer et al. 1999). Components of this integrin-dependent signal transduction pathway include various GTPase-activating proteins (Defilippi et al. 1999) which can alter effector- G-protein interactions (Hepler, 2000) and G-protein-mediated signal transduction. Activation of the downstream ERK1/2 and PI-3 kinase cell signalling cascades may also induce alterations in gene transcription and translation. However, the relatively rapid changes in β-AR signalling reported here argue against a significant increase in the number of β2-ARs resulting from new protein synthesis. Nevertheless, integrin engagement and clustering might alter the number of β2-ARs externalized to the sarcolemmal membrane surface without affecting the total number of receptors (see Hein & Kobilka, 1995). Clearly, future studies are required to evaluate each of these potential mechanisms.

Our present and previous (Wang et al. 2000) findings may be relevant to the dynamic and selective changes in β-AR signalling that occur in the failing heart. Thus, the failing human heart exhibits selective reduction in β1-ARs with little change in β2-AR density (Bristow et al. 1986; Ungerer et al. 1987). Functionally, the contractile response of the failing heart to β2-AR stimulation is significantly less depressed than that to β1-AR stimulation (Bristow et al. 1986). This selective change in β-AR signalling occurs in spite of the fact that the catalytic activity of AC is depressed in the failing human heart (Marzo et al. 1991). Moreover, in canine cardiac myocytes, zinterol elicited larger increases in contraction and intracellular Ca2+ release triggered by ICa,L in cells obtained from failing hearts than in those from healthy hearts, indicating enhanced β2-AR signalling in the failing heart (Altschuld et al. 1995). The failing heart is also associated with enhanced β-adrenergic receptor kinase (βARK) (Ungerer et al. 1987) which is responsible, in large part, for desensitization of β2-AR signalling (Muntz et al. 1994). Each of these changes in β-AR signalling of the failing heart is compatible with laminin-mediated changes in β-AR signalling. Thus, laminin binding to β1-integrins depresses AC activity (Wang et al. 2000), reduces β1-AR and enhances β2-AR signalling which is associated with desensitization. Ventricular pressure overload is associated with increases in ECM proteins and changes in integrin-binding proteins (Terracio et al. 1991) and integrin-mediated signalling pathways that are intimately associated with cytoskeletal proteins (Kuppuswamy et al. 1997). In addition, in rat ventricular myocytes adenovirus-mediated over-expression of β1-integrins augments the hypertrophic response, suggesting that integrins are key factors in the development of cardiac hypertrophy (Ross et al. 1998). We therefore propose that enhanced β1-integrin signalling may play an important role in the remodelling of β-AR signalling that occurs in the failing heart.

Acknowledgments

We thank Ms Holly Gray for her expert technical assistance and Dr Jörg Hüser for reading the manuscript and providing insightful comments. This work was supported by NIH grants HL27652 (S.L.L.) and HL34328 (A.M.S.).

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