Impaired cAMP-cGMP cross-talk during cardiac sympathetic dysautonomia

RNA Sequencing Reveals Novel Transcripts from Sympathetic Stellate Ganglia During Cardiac Sympathetic Hyperactivity

“…Sympathetic hyperactivity is a key feature of human hypertension that is also seen in animal models of cardiovascular disease 1 , 2 . In the spontaneously hypertensive rat (SHR), a genetic-based model of hypertension, dysautonomia occurs prior to increases in arterial blood pressure 3 – 5 . This neural phenotype is a powerful predictor of morbidity and mortality 6 – 8 .…”

“…In the spontaneously hypertensive rat (SHR), postganglionic sympathetic neurons (PGSNs) display increased [Ca 2+ ] i transients as a result of increased N -type voltage-gated Ca 2+ (Ica N , Ca v 2.2) channel activity 2 , 17 and impaired endoplasmic reticulum (ER) and mitochondrial Ca 2+ handling 4 . Cyclic nucleotides (cNs) and their effectors regulate Ca 2+ conductance predominantly via phosphorylation of ion channels, however, the relationship between cN second messenger signalling pathways and abnormal [Ca 2+ ] i is still poorly understood in disease 2 , 3 . Moreover, specific gene ontologies and protein-protein interactions linked to abnormal Ca 2+ regulation in sympathetic neurons from hypertensive states is lacking.…”

Neurotransmitter Switching Coupled to β-Adrenergic Signaling in Sympathetic Neurons in Prehypertensive States

“… 55 , 63 N-type calcium channelactivity is differentially regulated by PKA and PKG. 54 , 55 Therefore, we suggest that the isoprenaline-potentiated increases in [Ca 2+ ] i in pre-SHR neurons primarily occurs as a result of βAR–cAMP activation that increases PKA-dependent phosphorylation of N-type calcium channel (Ca v 2.2).…”

“… 64 , 65 We also report that in healthy ganglia, β 1 AR expression decreases with age, much like in the heart (Figure 1 ). Together, these data suggest that in diseased states, the potentiating effects of βAR agonists may be mediated through impaired second messengers coupled to cAMP and its effector PKA, probably via impairment of phosphodiesterases to hydrolyze cAMP 54 , 55 rather than the G-protein coupled receptors themselves.…”

“… 31 , 53 Recently, we demonstrated that decreased cGMP signaling leads to enhanced N-type Ca 2+ channel (Ca v 2.2) currents and that this effect may be ameliorated by artificially increasing cytosolic cGMP. 54 , 55 cN signaling is acutely regulated by phosphodiesterase enzymes, and in early prehypertensive states, phosphodiesterase signaling is impaired, resulting in an imbalance between cAMP and cGMP signaling. 54 We, therefore, sought to ask the question, could high levels of neurotransmitter release act in an autocrine or paracrine fashion to increase neuronal cAMP and potentiate neurotransmission in a feed-forward manner?…”