The Development of Compartmentation of cAMP Signaling in Cardiomyocytes: The Role of T-Tubules and Caveolae Microdomains

Abstract

3′-5′-cyclic adenosine monophosphate (cAMP) is a signaling messenger produced in response to the stimulation of cellular receptors, and has a myriad of functional applications depending on the cell type. In the heart, cAMP is responsible for regulating the contraction rate and force; however, cAMP is also involved in multiple other functions. Compartmentation of cAMP production may explain the specificity of signaling following a stimulus. In particular, transverse tubules (T-tubules) and caveolae have been found to be critical structural components for the spatial confinement of cAMP in cardiomyocytes, as exemplified by beta-adrenergic receptor (β-ARs) signaling. Pathological alterations in cardiomyocyte microdomain architecture led to a disruption in compartmentation of the cAMP signal. In this review, we discuss the difference between atrial and ventricular cardiomyocytes in respect to microdomain organization, and the pathological changes of atrial and ventricular cAMP signaling in response to myocyte dedifferentiation. In addition, we review the role of localized phosphodiesterase (PDE) activity in constraining the cAMP signal. Finally, we discuss microdomain biogenesis and maturation of cAMP signaling with the help of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Understanding these mechanisms may help to overcome the detrimental effects of pathological structural remodeling.

Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

“…Characteristic cardiomyocyte transverse tubules (T-tubules), caveolae and non-caveolae membrane microdomains contribute to ensure compartmentalized signal initiation [ 82 ]. Importantly, cholesterol and sphingolipid rich areas in the membrane, called lipid rafts, form gel-like, liquid-ordered domains that hinder membrane fluidity and prevent localized GPCRs to freely diffuse throughout the lipid bilayer [ 83 ].…”

Dual Activation of Phosphodiesterases 3 and 4 Regulates Basal Spontaneous Beating Rate of Cardiac Pacemaker Cells: Role of Compartmentalization?

“…In rabbit SANCs, caveolae increase the surface plasma membrane by ∼115 and ∼30% in VM ( Masson-Pevet et al, 1980 ). A variety of signaling molecules could be targeted to caveolae, including GPCRs, ACs, and PKA ( Rybin et al, 2000 ; Younes et al, 2008 ; Bhogal et al, 2018 ). The subpopulation of L-type Ca 2+ channels and HCN4 channels are also localized to caveolae ( Barbuti et al, 2004 ; Glukhov et al, 2015 ).…”

“…The subpopulation of L-type Ca 2+ channels and HCN4 channels are also localized to caveolae ( Barbuti et al, 2004 ; Glukhov et al, 2015 ). Caveolae have been identified as membrane subdomains that compartmentalize β-adrenergic receptor signaling and as negative regulators of cAMP accumulation in cardiac myocytes ( Rybin et al, 2000 ; Bhogal et al, 2018 ). Though activity of PDE3 and PDE4 in rabbit SA node has been measured ( Figure 1D ), there is no information on how much of that activity might be inside or outside of caveolae.…”

Modeling Depolarization Delay, Sodium Currents, and Electrical Potentials in Cardiac Transverse Tubules

“…Transverse (T-)tubules are deep invaginations of the lateral membrane of skeletal and cardiac muscle cells. In mammalian ventricular cardiomyocytes, T-tubules form a complex network throughout the cell, especially in species with high heart rates such as mice (Pinali et al, 2013;Jayasinghe et al, 2015), and carry many ion channels and regulatory proteins [reviewed in Bers (2002), Hong and Shaw (2017), and Bhogal et al (2018)]. Consequently, T-tubules function as a platform for excitation-contraction coupling and signaling, which is essential for the initiation and regulation of muscle contraction (Hong and Shaw, 2017).…”