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.

Keywords: arrhythmia; beta-adrenergic; cAMP; cardiac; electrophysiology; microdomains; sympathetic nervous system; t-tubules.

Figure 1

βAR pathways influencing electrophysiology–ion channel membrane complexes. This schematic indicates the suggested molecular complexes between ion channels and βAR subtypes where this is known, along with phosphorylation sites.

Figure 2

Downstream pathways influencing electrophysiology. This figure represents the pathways downstream of βAR. Kinase pathways and organellar involvement are indicated.

Figure 3

Existing experimental modalities with t-tubular resolution, permitting analysis of βAR physiology.