Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)-mediated Calcium Signaling and Arrhythmias in the Heart Evoked by β-Adrenergic Stimulation

Abstract

Background: Initial studies on cardiac NAADP signaling were published, but no role for NAADP in cardiac arrhythmias has been reported.Results: NAADP affects spontaneous diastolic Ca2+ transients in cardiac myocytes and arrhythmias in awake mice.Conclusion: Results indicate a pivotal role for NAADP in fine-tuning of cardiac excitation-contraction coupling.Significance: First evidence is reported for involvement of NAADP in cardiac arrhythmias evoked by β-adrenergic stimulation.

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

“…[255] Indeed, also, the simple NAADP derivative BZ194 has shown activity in T cells [256], autoimmune disease in vivo [257] and in vivo in the heart. [258] These are promising advances for the idea of pharmacological intervention in second messenger signalling and it should be clear that all of these techniques and ideas that move away from parent polyphosphate structures to more simple and drug-like compounds are in principle applicable to myo-inositol polyphosphates and their various targets, and obviously, perhaps more widely in the inositol series. Still more of interest from this general area is the observation that non-inositol based polyphosphates, e.g.…”

“…The cyclohexylidene acetal was removed and replaced with a benzylidene acetal attached to the Wang resin in a three step process to provide compound 257. DIBAL-H cleaved the benzylidene derivatives and benzoyl groups to give the 2-O-benzyl-intermediate (258) and expose the 3-hydroxy for further phosphorylation. Phosphorylation at 3-, 4-and 5-hydroxyl groups, and deprotection of the silicon protecting group allowed the introduction of the lipid derivative at the 1-hydroxyl.…”

NAD derived second messengers: Role in spontaneous diastolic Ca2+ transients in murine cardiac myocytes

“…Recently, we published that antagonism of NAADP by the novel NAADP antagonist BZ194 [9] decreased SCTs induced by strong ␤-adrenergic stimulation in ventricular cardiac myocytes and antagonized ␤-adrenoceptor evoked arrhythmia in awake mice, suggesting that NAADP plays a major pathological role in excitation-contraction coupling [28]. Another recent publication introduced high-affinity ADPRC inhibitors with unique specificity for a potential new ADPRC in heart; these compounds, e.g.…”

“…Both cADPR and NAADP were discovered as Ca 2+ mobilizing compounds in sea urchin eggs [22,23], but their function as endogenous Ca 2+ mobilizing second messengers has been observed in many cells and for many extracellular stimuli (reviewed in [13,11,21,41,29]). NAADP and cADPR have been reported to be involved in enhancement of the ␤-adrenoceptor-mediated positive inotropic response in heart [24], but also induction of NAADP-dependent spontaneous diastolic Ca 2+ transients (SCTs) was published [28]. A number of reports suggest a function for NAADP in the heart: (i) heart microsomes respond to NAADP by Ca 2+ release [27], (ii) NAADP increased the open probability of RyR2 incorporated into lipid planar bilayers [27], and (iii) high affinity binding sites for NAADP were detected in cardiac microsomes [1].…”

“…Strong ␤-adrenergic stimulation induced spontaneous diastolic Ca 2+ transients (SCTs) in electrically paced murine cardiac myocytes [28]. To obtain further insights into the underlying mechanism, we developed a method for a simultaneous analysis, in which the free luminal Ca 2+ concentration in the sarcoplasmic reticulum (SR) ([Ca 2+ ] SR ) and the free cytosolic Ca 2+ concentration ([Ca 2+ ] i ) were measured in parallel in the same cell.…”