Dysregulation of neuronal Ca2+ linked channel linked to heightened sympathetic phenotype in prohypertensive states

Journal article

Hypertension is associated with impaired nitric oxide (NO) - cyclic nucleotide (CN) - coupled intracellular calcium (Ca2+) homeostasis that enhances cardiac sympathetic neurotransmission. Because neuronal membrane CA2+ currents are reduced by NO-activated S-nitrosylation, we tested whether CNs affect membrane channel conductance directly in neurons isolated from the stellate ganglia of spontaneously hypertensive rats (SHRs) and their normotensive controls. Using voltage-clamp and cAMP-protein kinase A (PKA) FRET sensors, we hypothesized that impaired CN regulation provides a direct link to abnormal signaling of neuronal calcium channels in the SHR and that targeting cGMP can restore the channel phenotype. We found significantly larger whole-cell Ca2+ currents from diseased neurons that were largely mediated by the N-type Ca2+ channel (Cav2.2). Elevating cGMP restored the SHR Ca2+ current to levels seen in normal neurons that were not affected by cGMP. cGMP also decreased cAMP levels and PKA activity in diseased neurons. In contrast, cAMP-PKA activity was increased in normal neurons, suggesting differential swtching in phosphodiesterase (PDE) activity. PDE2A inhibition enhanced the Ca2+ current in normal neurons to a conductance similar to that seen in SHR neurons whereas the inhibitor slightly decreased the current in diseased neurons. Pharmacological evidence supported a switching a cGMP acting via PDE3 in control neurons to PDE2A in SHR neurons in the modulation of the Ca2+ current. Our data suggest that a disturbance in the regulation of PDE-coupled CNs linked to N-type Ca2+ channels is an early hallmark of the prohypertensive phenotype associated with intracellular Ca2+ impairment underpinning sympathetic dysautonomia.

Authors: Paterson, D; Larsen, H; Bardsley, E; Lefkimmiatis, K

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Society for Neuroscience
• Journal: Journal of Neuroscience
• Volume: 36
• Issue: 33
• Publication date: 2016-08-17
• Acceptance date: 2016-05-27
• DOI: 10.1523/JNEUROSCI.1059-16.2016
• Keywords: dysautonomia; N-type Ca2+ channel; sympathetic; hypertension; autonomic nervous system; cGMP