Recent studies of the molecular mechanism of lusitropy due to phosphorylation of cardiac troponin I by protein kinase A

Autor: Steven Marston
Rok vydání: 2022
Předmět:
Zdroj: Journal of Muscle Research and Cell Motility.
ISSN: 1573-2657
0142-4319
DOI: 10.1007/s10974-022-09630-4
Popis: Ca2+ acts on troponin and tropomyosin to switch the thin filament on and off, however in cardiac muscle a more graded form of regulation is essential to tailor cardiac output to the body’s needs. This is achieved by the action of adrenaline on β1 receptors of heart muscle cells leading to enhanced contractility, faster heart rate and faster relaxation (lusitropy) via activation of the cyclic AMP-dependent protein kinase, PKA. PKA phosphorylates serines 22 and 23 in the N-terminal peptide of cardiac troponin I. As a consequence the rate of Ca2+release from troponin is increased. This is the key determinant of lusitropy. The molecular mechanism of this process has remained unknown long after the mechanism of the troponin Ca2+ switch itself was defined. Investigation of this subtle process at the atomic level poses a challenge, since the change in Ca2+-sensitivity is only about twofold and key parts of the troponin modulation and regulation system are disordered and cannot be fully resolved by conventional structural approaches. We will review recent studies using molecular dynamics simulations together with functional, cryo-em and NMR techniques that have started to give us a precise picture of how phosphorylation of troponin I modulates the dynamics of troponin to produce the lusitropic effect.
Databáze: OpenAIRE
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