L3. Nucleotide signalling in the heart Flashcards
What is the prototypical second messenger in cells?
Cyclic AMP (cAMP)
Who discovered cAMP and won the Nobel Prize for it?
Earl W. Sutherland in 1971
What is the primary function of cyclic nucleotides like cAMP?
To act as intracellular second messengers for signal transduction
Which enzyme synthesizes cAMP from ATP?
Adenylyl cyclase
Which enzyme degrades cAMP?
Phosphodiesterase (PDE)
Why is the hydrophilic nature of cAMP important?
It allows for compartmentalized signaling within the cell
What does cAMP primarily activate?
Protein kinase A (PKA)
How does PKA achieve signal specificity?
Through spatial confinement via anchoring proteins like AKAPs
What is the role of AKAPs in cAMP signaling?
To localize PKA to specific subcellular compartments
Name a few cellular processes regulated by cAMP.
Memory, metabolism, cell growth, and gene transcription
How does cAMP influence cardiac myocytes during stress?
It increases contractility and heart rate
What is the effect of PKA phosphorylation on phospholamban?
It enhances calcium uptake in the sarcoplasmic reticulum
Why is compartmentalization important in cAMP signaling?
It ensures specificity despite cAMP being a common messenger for multiple hormones
What are signalosomes?
Multi-protein complexes that organize signaling elements for localized cAMP effects
How do phosphodiesterases contribute to compartmentalization?
By degrading cAMP locally, maintaining concentration gradients
What technique is used to visualize cAMP gradients in cells?
FRET-based imaging
How does IBMX affect cAMP gradients?
It inhibits phosphodiesterases, disrupting compartmentalization
What is the role of liquid condensates in cAMP signaling?
They buffer cAMP to slow diffusion and maintain local signaling
What happens to cAMP signaling in heart failure?
There is reduced cAMP-mediated signaling and receptor desensitization
Why did PDE3 inhibitors fail in long-term heart failure trials?
They caused harmful side effects despite short-term benefits
What is the paradox of cAMP-raising drugs in heart failure?
They improve contractility short-term but increase long-term mortality
What is the function of phase-separated liquid condensates in cells?
To compartmentalize and buffer second messengers like cAMP
What is the effect of β2-adrenergic receptor redistribution in failing hearts?
It disrupts localized signaling, contributing to disease pathology
How do cAMP and cyclic GMP differ in their signaling roles?
cAMP regulates contractility, while cGMP often has protective effects
Which enzymes generate cGMP?
Soluble guanylate cyclase and particulate guanylate cyclase
How does sildenafil (Viagra) affect the heart in animal models?
It shows cardioprotective effects by enhancing cGMP signaling
Why might PDE9 inhibitors succeed where PDE5 inhibitors failed in heart failure?
PDE9 regulates a distinct pool of cGMP involved in heart protection
What experiment confirmed cAMP compartmentalization in myocytes?
FRET imaging with phosphodiesterase inhibitors like IBMX
What happens when AKAP18δ is knocked down?
Calcium reuptake in the sarcoplasmic reticulum slows significantly
How are PDE isoforms localized within cells?
They have unique regulatory domains targeting specific cellular locations
What is the role of troponin phosphorylation in myocytes?
It reduces calcium affinity to promote relaxation
How does phosphorylation of L-type calcium channels affect the heart?
It increases calcium influx, enhancing contractility
Why is cAMP compartmentalization necessary for maximal contractility?
It ensures precise timing and location of calcium signaling
What structural changes occur in heart failure related to cAMP signaling?
Disruption of receptor and PDE compartmentalization
How does β2-adrenergic signaling protect the heart?
By activating cardioprotective pathways via localized cAMP pools
What did SICM imaging reveal about heart failure?
Redistribution of β2-adrenergic receptors and altered cAMP signaling
How can understanding PDE localization improve drug design?
By targeting specific PDEs to enhance beneficial effects and avoid harm
What is the significance of signalosome disruption in heart failure?
It contributes to loss of signal specificity and worsens pathology
What is the future direction for cyclic nucleotide research?
Developing drugs targeting localized signaling domains
What is the effect of cyclic AMP on ion channels?
It modulates their activity, impacting electrical signaling
