Transgenic manipulation of β-adrenergic receptor kinase modifies cardiac myocyte contraction to norepinephrine

Donna Hope Korzick, Rui Ping Xiao, Bruce D. Ziman, Walter J. Koch, Robert J. Lefkowitz, Edward G. Lakatta

Research output: Contribution to journalArticle

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Abstract

To determine the direct functional significance of the β-adrenergic receptor (AR) kinase 1 (βARK1) on myocardial performance in the absence of tonic sympathoadrenal neural activation and mechanical loading, we measured the contractile responses to acute β1-AR stimulation in left ventricular myocytes isolated from nontransgenic control (NTG) and transgenic mice overexpressing either βARK1 (TGβK12) or a βARK1 inhibitor (TGMini27). Contractile response to five concentrations (10-8-10-7 M) of the β1-AR agonist norepinephrine (NE) plus prazosin (10-6 M) was measured after a 60- s rest, i.e., rested-state contraction (RSC), and during steady-state contraction (SSC) stimulation at 0.5 Hz (23°C). At baseline, resting cell length was significantly greater in TGβK12 myocytes (P < 0.05); however, there were no significant differences in RSC or SSC among NTG, TGβK12, or TGMini27 mice. On the other hand, both the dose-response curve and kinetics for the NE-induced SSC response normalized to RSC (SSC/RSC) were significantly different among experimental groups (P < 0.001). Specifically, maximal SSC induced by NE in myocytes isolated from TGβK12 was only 70% of the response observed in NTG cells and 50% of the response measured in TGMini27. These data suggest that 1) in the absence of circulating catecholamines or basal sympathetic tone, βARK1 actions in single myocytes are minimal, and 2) substantial functional βARK1 modulation of β1AR signaling occurs in cardiac myocytes even during short-term β1-AR stimulation. These results are consistent with a role for agonist-induced phosphorylation and desensitization of cardiac β1-ARs by βARK1 in single myocytes and highlight the potential functional importance of βARK1 as a critical determinant of the cardiac β1-AR contractile response.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume272
Issue number1 41-1
StatePublished - Feb 20 1997

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Cardiac Myocytes
Adrenergic Receptors
Norepinephrine
Phosphotransferases
Muscle Cells
Adrenergic Agonists
Prazosin
Amberlite XAD-2 resin
Transgenic Mice
Catecholamines
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Korzick, Donna Hope ; Xiao, Rui Ping ; Ziman, Bruce D. ; Koch, Walter J. ; Lefkowitz, Robert J. ; Lakatta, Edward G. / Transgenic manipulation of β-adrenergic receptor kinase modifies cardiac myocyte contraction to norepinephrine. In: American Journal of Physiology - Heart and Circulatory Physiology. 1997 ; Vol. 272, No. 1 41-1.
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abstract = "To determine the direct functional significance of the β-adrenergic receptor (AR) kinase 1 (βARK1) on myocardial performance in the absence of tonic sympathoadrenal neural activation and mechanical loading, we measured the contractile responses to acute β1-AR stimulation in left ventricular myocytes isolated from nontransgenic control (NTG) and transgenic mice overexpressing either βARK1 (TGβK12) or a βARK1 inhibitor (TGMini27). Contractile response to five concentrations (10-8-10-7 M) of the β1-AR agonist norepinephrine (NE) plus prazosin (10-6 M) was measured after a 60- s rest, i.e., rested-state contraction (RSC), and during steady-state contraction (SSC) stimulation at 0.5 Hz (23°C). At baseline, resting cell length was significantly greater in TGβK12 myocytes (P < 0.05); however, there were no significant differences in RSC or SSC among NTG, TGβK12, or TGMini27 mice. On the other hand, both the dose-response curve and kinetics for the NE-induced SSC response normalized to RSC (SSC/RSC) were significantly different among experimental groups (P < 0.001). Specifically, maximal SSC induced by NE in myocytes isolated from TGβK12 was only 70{\%} of the response observed in NTG cells and 50{\%} of the response measured in TGMini27. These data suggest that 1) in the absence of circulating catecholamines or basal sympathetic tone, βARK1 actions in single myocytes are minimal, and 2) substantial functional βARK1 modulation of β1AR signaling occurs in cardiac myocytes even during short-term β1-AR stimulation. These results are consistent with a role for agonist-induced phosphorylation and desensitization of cardiac β1-ARs by βARK1 in single myocytes and highlight the potential functional importance of βARK1 as a critical determinant of the cardiac β1-AR contractile response.",
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Transgenic manipulation of β-adrenergic receptor kinase modifies cardiac myocyte contraction to norepinephrine. / Korzick, Donna Hope; Xiao, Rui Ping; Ziman, Bruce D.; Koch, Walter J.; Lefkowitz, Robert J.; Lakatta, Edward G.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 272, No. 1 41-1, 20.02.1997.

Research output: Contribution to journalArticle

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T1 - Transgenic manipulation of β-adrenergic receptor kinase modifies cardiac myocyte contraction to norepinephrine

AU - Korzick, Donna Hope

AU - Xiao, Rui Ping

AU - Ziman, Bruce D.

AU - Koch, Walter J.

AU - Lefkowitz, Robert J.

AU - Lakatta, Edward G.

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AB - To determine the direct functional significance of the β-adrenergic receptor (AR) kinase 1 (βARK1) on myocardial performance in the absence of tonic sympathoadrenal neural activation and mechanical loading, we measured the contractile responses to acute β1-AR stimulation in left ventricular myocytes isolated from nontransgenic control (NTG) and transgenic mice overexpressing either βARK1 (TGβK12) or a βARK1 inhibitor (TGMini27). Contractile response to five concentrations (10-8-10-7 M) of the β1-AR agonist norepinephrine (NE) plus prazosin (10-6 M) was measured after a 60- s rest, i.e., rested-state contraction (RSC), and during steady-state contraction (SSC) stimulation at 0.5 Hz (23°C). At baseline, resting cell length was significantly greater in TGβK12 myocytes (P < 0.05); however, there were no significant differences in RSC or SSC among NTG, TGβK12, or TGMini27 mice. On the other hand, both the dose-response curve and kinetics for the NE-induced SSC response normalized to RSC (SSC/RSC) were significantly different among experimental groups (P < 0.001). Specifically, maximal SSC induced by NE in myocytes isolated from TGβK12 was only 70% of the response observed in NTG cells and 50% of the response measured in TGMini27. These data suggest that 1) in the absence of circulating catecholamines or basal sympathetic tone, βARK1 actions in single myocytes are minimal, and 2) substantial functional βARK1 modulation of β1AR signaling occurs in cardiac myocytes even during short-term β1-AR stimulation. These results are consistent with a role for agonist-induced phosphorylation and desensitization of cardiac β1-ARs by βARK1 in single myocytes and highlight the potential functional importance of βARK1 as a critical determinant of the cardiac β1-AR contractile response.

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