Electrophysiological Remodeling: Cardiac T-Tubules and ß-Adrenoceptors

Abstract

Beta-adrenoceptors (βAR) are often viewed as archetypal G-protein coupled receptors. Over the past fifteen years, investigations in cardiovascular biology have provided remarkable insights into this receptor family. These studies have shifted pharmacological dogma, from one which centralized the receptor to a new focus on structural micro-domains such as caveolae and t-tubules. Important studies have examined, separately, the structural compartmentation of ion channels and βAR. Despite links being assumed, relatively few studies have specifically examined the direct link between structural remodeling and electrical remodeling with a focus on βAR. In this review, we will examine the nature of receptor and ion channel dysfunction on a substrate of cardiomyocyte microdomain remodeling, as well as the likely ramifications for cardiac electrophysiology. We will then discuss the advances in methodologies in this area with a specific focus on super-resolution microscopy, fluorescent imaging, and new approaches involving microdomain specific, polymer-based agonists. The advent of powerful computational modelling approaches has allowed the science to shift from purely empirical work, and may allow future investigations based on prediction. Issues such as the cross-reactivity of receptors and cellular heterogeneity will also be discussed. Finally, we will speculate as to the potential developments within this field over the next ten years.

Phosphodiesterases 4B and 4D Differentially Regulate cAMP Signaling in Calcium Handling Microdomains of Mouse Hearts

“…To investigate the impact of PDE4B and PDE4D on cAMP dynamics at the caveolin-rich plasma membrane microdomains, real-time FRET measurements were performed using CMs freshly isolated from transgenic mice expressing the highly sensitive membrane targeted FRET-based biosensor pmEpac1 in wildtype vs. PDE4B or PDE4D null background. Although not directly co-localized with the LTCCs, the pmEpac1 biosensor is a suitable tool to monitor cAMP dynamics in the caveolin-rich plasma membrane microdomains including T-tubules where these channels are located at high density [ 33 ].…”

“…Although not directly co-localized with the LTCCs, the pmEpac1 biosensor is a suitable tool to monitor cAMP dynamics in the caveolin-rich plasma membrane microdomains including T-tubules where these channels are located at high density [33].…”

Electrical Remodelling in Cardiac Disease

“…β-Adrenoceptors and ion channels are located in close vicinity to each other within the transverse-axial tubule system. Therefore, de-tubulation of cardiomyocytes associated with cardiac disease is linked to electrical remodelling with arrhythmogenic potential [19]. Disruption of the transverse-axial system as observed for instance in heart failure or atrial fibrillation is associated with dysfunction of Ca 2+ handling proteins that may lead to Ca 2+ -driven proarrhythmic effects [20].…”