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Researchers used an optogenetic tool (PAC(S27A) mutant) to control intracellular cAMP levels with light, demonstrating that this activation stimulates HCN channels in both cardiac cells and brain neurons. Light-induced cAMP elevation increased heart beating rates in cardiomyocytes and induced rotational behavior in mice when expressed in the substantia nigra. In a Parkinson's disease mouse model, this optogenetic activation partially restored motor function and increased HCN2 channel expression in the basal ganglia.
Why it matters
This work establishes a proof-of-concept for using optogenetic modulation of cAMP-HCN signaling to treat cardiac arrhythmias and Parkinson's disease. While direct clinical translation of optogenetics faces significant hurdles, these findings may guide development of pharmacological approaches targeting the cAMP-HCN pathway for neurological and cardiac disorders.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Cyclic adenosine monophosphate (cAMP) is a second messenger that regulates various cellular processes, including the activity of hyperpolarization-activated channels (HCN), which are implicated in cardiac physiology and neurodegenerative diseases such as Parkinson’s disease (PD). In this study, we used a photoactivated adenylyl cyclase (PAC) S27A mutant to optogenetically control intracellular cAMP levels. We demonstrated that light-induced elevation of cAMP activated HCN4 channels, leading to increased beating rates in cardiomyocytes. Unilateral expression of PAC(S27A) in the substantia nigra pars compacta of mice induced rotation behavior upon light stimulation, which could be attenuated by HCN inhibitors. Furthermore, PAC(S27A) activation partially recovered motor deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model, accompanied by increased HCN2 channel expression in ipsilateral basal ganglia. Our findings highlight the potential of using optogenetics to modulate cAMP and HCN channel activity for the treatment of cardiac and neurological disorders.