Figure 8.

Schematic depiction of changes in structure and location of β2ARs during progression of heart failure. In normal cardiomyocytes the external surface structure (Z-grooves and crests) and internal TAT network, consisting of T-tubules and longitudinal elements, is intact and β₂AR are located exclusively inside T-tubules; JPH2 connects T-tubules with the SR; cAMP does not diffuse far from the site of β₂AR activation; and Cav 3 is predominantly in the membrane of cells. In heart failure the surface structure regularity deteriorates progressively; First, after only 4 weeks of MI, JPH2 is downregulated; Second, as early as 4 weeks, the amount of longitudinal elements increases, perhaps as a compensatory mechanism; At the same time β₂AR-cAMP responses start to appear at the crest, and the cAMP response is no longer confined to the site of β₂AR activation; Later, at 16 weeks the deterioration of surface and T-tubule structure continues, overall Cav 3 levels increase while the amount of longitudinal element decreases, and the overall cAMP production decreases as well, which may be due to inefficient β₂AR associated AC signalling.