Modeling ß1-adrenergic receptor blockers and polymorphisms in cardiac myocytes

Duration: 16 mins 51 secs

Share this media item:

Embed this media item:

<iframe width="_width_" height="_height_" src="https://sms.cam.ac.uk/media/649526/embed" frameborder="0" scrolling="no" allowfullscreen></iframe>

Choose size:

About this item

Available Formats

About this item

Description:	Saucerman, J (Virginia) Monday 20 July 2009, 11:30-11:45

Created:

2009-07-22 16:43

Collection:

Cardiac Physiome Project

Publisher:

Isaac Newton Institute

Saucerman, J (Virginia)

Language:

eng (English)

Credits:

Author:

Saucerman, J


Abstract:	Modeling β1¬-adrenergic receptor blockers and polymorphisms in cardiac myocytes Robert Amanfu, Ryan Connolly, Sean Meredith, and Jeff Saucerman β-blockers are the one of the most effective medications for heart failure. But their success appears counterintuitive because they block the β1-adrenergic signaling pathway in cardiac myocytes, which enhances cardiac contractility. To evaluate mechanisms of β-blocker efficacy, we extended our cardiac myocyte β1-adrenergic signaling model using an extended ternary complex receptor model. This receptor model includes spontaneous switching between the active and inactive receptor conformations crucial for accurate representation of β-blockers and receptor polymorphisms. We determined parameters from the literature to model 11 agonists and 10 β-blockers and validated against a range of published experimental data. This new model predicts that at intermediate concentrations, β-blockers may protect the adrenergic pathway from chronic stress while paradoxically sensitizing the pathway to acute stress (like exercise). The Arg389 receptor polymorphism (prevalence ~50%) was predicted to constitutively stimulate calcium transients by 68%, which was restored to the activity of the wild type receptor by administration of 1 µM β-blocker (propranolol). Model predictions are being validated experimentally. These simulations are a first step towards evaluating personalized β-blocker therapies with computational models.

Abstract:

Modeling β1¬-adrenergic receptor blockers and polymorphisms in cardiac myocytes Robert Amanfu, Ryan Connolly, Sean Meredith, and Jeff Saucerman β-blockers are the one of the most effective medications for heart failure. But their success appears counterintuitive because they block the β1-adrenergic signaling pathway in cardiac myocytes, which enhances cardiac contractility. To evaluate mechanisms of β-blocker efficacy, we extended our cardiac myocyte β1-adrenergic signaling model using an extended ternary complex receptor model. This receptor model includes spontaneous switching between the active and inactive receptor conformations crucial for accurate representation of β-blockers and receptor polymorphisms. We determined parameters from the literature to model 11 agonists and 10 β-blockers and validated against a range of published experimental data. This new model predicts that at intermediate concentrations, β-blockers may protect the adrenergic pathway from chronic stress while paradoxically sensitizing the pathway to acute stress (like exercise). The Arg389 receptor polymorphism (prevalence ~50%) was predicted to constitutively stimulate calcium transients by 68%, which was restored to the activity of the wild type receptor by administration of 1 µM β-blocker (propranolol). Model predictions are being validated experimentally. These simulations are a first step towards evaluating personalized β-blocker therapies with computational models.

Available Formats

Format	Quality	Bitrate	Size
MPEG-4 Video	480x360	1.83 Mbits/sec	231.31 MB	View	Download
WebM	450x360	878.13 kbits/sec	107.41 MB	View	Download
Flash Video	480x360	805.32 kbits/sec	98.99 MB	View	Download
iPod Video	320x240	504.51 kbits/sec	62.02 MB	View	Download
QuickTime	480x360	506.72 kbits/sec	62.29 MB	View	Download
MP3	44100 Hz	125.0 kbits/sec	15.17 MB	Listen	Download
Windows Media Video		477.72 kbits/sec	58.72 MB	View	Download
Auto *	(Allows browser to choose a format it supports)