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Increased expression of the cardiac L-type calcium channel in estrogen receptor-deficient mice.

Johnson BD, Zheng W, Korach KS, Scheuer T, Catterall WA, Rubanyi GM - J. Gen. Physiol. (1997)

Bottom Line: Steroid hormones control the expression of many cellular regulators, and a role for estrogen in cardiovascular function and disease has been well documented.Whole-cell patch clamp of acutely dissociated adult cardiac ventricular myocytes indicated that Ca2+ channel current was increased by 49% and action potential duration was increased by 75%.These results show that the membrane density of the cardiac L-type Ca2+ channel is regulated by the estrogen receptor and suggest that decreased estrogen may lead to an increase in the number of cardiac L-type Ca2+ channels, abnormalities in cardiac excitability, and increased risk of arrhythmia and cardiovascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.

ABSTRACT
Steroid hormones control the expression of many cellular regulators, and a role for estrogen in cardiovascular function and disease has been well documented. To address whether the activity of the L-type Ca2+ channel, a critical element in cardiac excitability and contractility, is altered by estrogen and its nuclear receptor, we examined cardiac myocytes from male mice in which the estrogen receptor gene had been disrupted (ERKO mice). Binding of dihydropyridine Ca2+ channel antagonist isradipine (PN200-110) was increased 45.6% in cardiac membranes from the ERKO mice compared to controls, suggesting that a lack of estrogen receptors in the heart increased the number of Ca2+ channels. Whole-cell patch clamp of acutely dissociated adult cardiac ventricular myocytes indicated that Ca2+ channel current was increased by 49% and action potential duration was increased by 75%. Examination of electrocardiogram parameters in ERKO mice showed a 70% increase in the QT interval without significant changes in PQ or QRS intervals. These results show that the membrane density of the cardiac L-type Ca2+ channel is regulated by the estrogen receptor and suggest that decreased estrogen may lead to an increase in the number of cardiac L-type Ca2+ channels, abnormalities in cardiac excitability, and increased risk of arrhythmia and cardiovascular disease.

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Dihydropyridine binding to cardiac membranes. Saturation binding of the L-type Ca2+-channel dihydropyridine ligand  3H(+)-PN200-110 to cardiac membranes was analyzed in hearts  isolated from eight control and eight ERKO male mice. (A) Comparison of Scatchard plots of 3H(+)-PN200-110 binding to cardiac  membranes from one control and one ERKO mouse shows an elevated number of binding sites (Bmax: intersection of plot with  the x-axis) but similar binding affinity (Kd: slope of plot) in ERKO  hearts. (B) Mean values (± SEM) of eight experiments reveal statistically significant increase of Bmax (by 45.6%)(*, p < 0.05), but  no significant change in Kd or Hill-coefficient of 3H(+)-PN200-110  binding to cardiac membranes from ERKO hearts.
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Figure 1: Dihydropyridine binding to cardiac membranes. Saturation binding of the L-type Ca2+-channel dihydropyridine ligand 3H(+)-PN200-110 to cardiac membranes was analyzed in hearts isolated from eight control and eight ERKO male mice. (A) Comparison of Scatchard plots of 3H(+)-PN200-110 binding to cardiac membranes from one control and one ERKO mouse shows an elevated number of binding sites (Bmax: intersection of plot with the x-axis) but similar binding affinity (Kd: slope of plot) in ERKO hearts. (B) Mean values (± SEM) of eight experiments reveal statistically significant increase of Bmax (by 45.6%)(*, p < 0.05), but no significant change in Kd or Hill-coefficient of 3H(+)-PN200-110 binding to cardiac membranes from ERKO hearts.

Mentions: The number of L-type Ca2+ channels in the hearts of control and ERKO mice was first measured directly by binding of the dihydropyridine Ca2+ channel antagonist PN200-110. Dihydropyridines bind specifically and with high affinity to L-type Ca2+ channels with a 1:1 stoichiometry. The number of specific binding sites for PN200-110 (Bmax) in cardiac membranes was increased 45.6% in ERKO mice without a change in the affinity (Kd) of the channel for the dihydropyridine (Fig. 1). This increase in the number of Ca2+ channels was not due to cardiac hypertrophy in ERKO mice since neither the weight of the heart nor amount of protein in each heart was changed.


Increased expression of the cardiac L-type calcium channel in estrogen receptor-deficient mice.

Johnson BD, Zheng W, Korach KS, Scheuer T, Catterall WA, Rubanyi GM - J. Gen. Physiol. (1997)

Dihydropyridine binding to cardiac membranes. Saturation binding of the L-type Ca2+-channel dihydropyridine ligand  3H(+)-PN200-110 to cardiac membranes was analyzed in hearts  isolated from eight control and eight ERKO male mice. (A) Comparison of Scatchard plots of 3H(+)-PN200-110 binding to cardiac  membranes from one control and one ERKO mouse shows an elevated number of binding sites (Bmax: intersection of plot with  the x-axis) but similar binding affinity (Kd: slope of plot) in ERKO  hearts. (B) Mean values (± SEM) of eight experiments reveal statistically significant increase of Bmax (by 45.6%)(*, p < 0.05), but  no significant change in Kd or Hill-coefficient of 3H(+)-PN200-110  binding to cardiac membranes from ERKO hearts.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2233789&req=5

Figure 1: Dihydropyridine binding to cardiac membranes. Saturation binding of the L-type Ca2+-channel dihydropyridine ligand 3H(+)-PN200-110 to cardiac membranes was analyzed in hearts isolated from eight control and eight ERKO male mice. (A) Comparison of Scatchard plots of 3H(+)-PN200-110 binding to cardiac membranes from one control and one ERKO mouse shows an elevated number of binding sites (Bmax: intersection of plot with the x-axis) but similar binding affinity (Kd: slope of plot) in ERKO hearts. (B) Mean values (± SEM) of eight experiments reveal statistically significant increase of Bmax (by 45.6%)(*, p < 0.05), but no significant change in Kd or Hill-coefficient of 3H(+)-PN200-110 binding to cardiac membranes from ERKO hearts.
Mentions: The number of L-type Ca2+ channels in the hearts of control and ERKO mice was first measured directly by binding of the dihydropyridine Ca2+ channel antagonist PN200-110. Dihydropyridines bind specifically and with high affinity to L-type Ca2+ channels with a 1:1 stoichiometry. The number of specific binding sites for PN200-110 (Bmax) in cardiac membranes was increased 45.6% in ERKO mice without a change in the affinity (Kd) of the channel for the dihydropyridine (Fig. 1). This increase in the number of Ca2+ channels was not due to cardiac hypertrophy in ERKO mice since neither the weight of the heart nor amount of protein in each heart was changed.

Bottom Line: Steroid hormones control the expression of many cellular regulators, and a role for estrogen in cardiovascular function and disease has been well documented.Whole-cell patch clamp of acutely dissociated adult cardiac ventricular myocytes indicated that Ca2+ channel current was increased by 49% and action potential duration was increased by 75%.These results show that the membrane density of the cardiac L-type Ca2+ channel is regulated by the estrogen receptor and suggest that decreased estrogen may lead to an increase in the number of cardiac L-type Ca2+ channels, abnormalities in cardiac excitability, and increased risk of arrhythmia and cardiovascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.

ABSTRACT
Steroid hormones control the expression of many cellular regulators, and a role for estrogen in cardiovascular function and disease has been well documented. To address whether the activity of the L-type Ca2+ channel, a critical element in cardiac excitability and contractility, is altered by estrogen and its nuclear receptor, we examined cardiac myocytes from male mice in which the estrogen receptor gene had been disrupted (ERKO mice). Binding of dihydropyridine Ca2+ channel antagonist isradipine (PN200-110) was increased 45.6% in cardiac membranes from the ERKO mice compared to controls, suggesting that a lack of estrogen receptors in the heart increased the number of Ca2+ channels. Whole-cell patch clamp of acutely dissociated adult cardiac ventricular myocytes indicated that Ca2+ channel current was increased by 49% and action potential duration was increased by 75%. Examination of electrocardiogram parameters in ERKO mice showed a 70% increase in the QT interval without significant changes in PQ or QRS intervals. These results show that the membrane density of the cardiac L-type Ca2+ channel is regulated by the estrogen receptor and suggest that decreased estrogen may lead to an increase in the number of cardiac L-type Ca2+ channels, abnormalities in cardiac excitability, and increased risk of arrhythmia and cardiovascular disease.

Show MeSH
Related in: MedlinePlus