Abnormal cyclic nucleotide signaling at the outer mitochondrial membrane in sympathetic neurons during the early stages of hypertension

<strong>Background:<br></strong> Disruption of cyclic nucleotide signaling in sympathetic postganglionic neurons contributes to impaired intracellular calcium handling (Ca2+) and the development of dysautonomia during the early stages of hypertension, although how this occurs is po...

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Main Authors: Li, D, Liu, K, Davis, H, Robertson, C, Neely, OC, Tarafdar, A, Li, N, Lefkimmiatis, K, Zaccolo, M, Paterson, DJ
Format: Journal article
Language:English
Published: American Heart Association 2022
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author Li, D
Liu, K
Davis, H
Robertson, C
Neely, OC
Tarafdar, A
Li, N
Lefkimmiatis, K
Zaccolo, M
Paterson, DJ
author_facet Li, D
Liu, K
Davis, H
Robertson, C
Neely, OC
Tarafdar, A
Li, N
Lefkimmiatis, K
Zaccolo, M
Paterson, DJ
author_sort Li, D
collection OXFORD
description <strong>Background:<br></strong> Disruption of cyclic nucleotide signaling in sympathetic postganglionic neurons contributes to impaired intracellular calcium handling (Ca2+) and the development of dysautonomia during the early stages of hypertension, although how this occurs is poorly understood. Emerging evidence supports the uncoupling of signalosomes in distinct cellular compartments involving cyclic nucleotide–sensitive PDEs (phosphodiesterases), which may underpin the autonomic phenotype in stellate neurons. <br><strong> Methods:<br></strong> Using a combination of single-cell RNA sequencing together with Forster resonance energy transfer–based sensors to monitor cyclic adenosine 3’,5’-monophosphate, PKA (protein kinase A)-dependent phosphorylation and cGMP (cyclic guanosine 3’,5’-monophosphate), we tested the hypothesis that dysregulation occurs in a sub-family of PDEs in the cytosol and outer mitochondrial membrane of neurons from the stellate ganglion. <br><strong> Results:<br></strong> PDE2A, 6D, 7A, 9A genes were highly expressed in young Wistar neurons and also conserved in neurons from spontaneously hypertensive rats (SHRs). In stellate neurons from prehypertensive SHRs, we found the levels of cyclic adenosine 3’,5’-monophosphate and cGMP at the outer mitochondrial membrane were decreased compared with normal neurons. The reduced cyclic adenosine 3’,5’-monophosphate response was due to the hydrolytic activity of overexpressed PDE2A2 located at the mitochondria. Normal cyclic adenosine 3’,5’-monophosphate levels were re-established by inhibition of PDE2A. There was also a greater PKA-dependent phosphorylation in the cytosol and at the outer mitochondrial membrane in spontaneously hypertensive rat neurons, where this response was regulated by protein phosphatases. The cGMP response was only restored by inhibition of PDE6. <br><strong> Conclusions:<br></strong> When taken together, these results suggest that site-specific inhibition of PDE2A and PDE6D at the outer mitochondrial membrane may provide a therapeutic target to ameliorate cardiac sympathetic impairment during the onset of hypertension.
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spelling oxford-uuid:ae6c6dc6-6c0a-4449-8fc3-89b0677799d32022-07-13T16:48:03ZAbnormal cyclic nucleotide signaling at the outer mitochondrial membrane in sympathetic neurons during the early stages of hypertensionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ae6c6dc6-6c0a-4449-8fc3-89b0677799d3EnglishSymplectic ElementsAmerican Heart Association2022Li, DLiu, KDavis, HRobertson, CNeely, OCTarafdar, ALi, NLefkimmiatis, KZaccolo, MPaterson, DJ<strong>Background:<br></strong> Disruption of cyclic nucleotide signaling in sympathetic postganglionic neurons contributes to impaired intracellular calcium handling (Ca2+) and the development of dysautonomia during the early stages of hypertension, although how this occurs is poorly understood. Emerging evidence supports the uncoupling of signalosomes in distinct cellular compartments involving cyclic nucleotide–sensitive PDEs (phosphodiesterases), which may underpin the autonomic phenotype in stellate neurons. <br><strong> Methods:<br></strong> Using a combination of single-cell RNA sequencing together with Forster resonance energy transfer–based sensors to monitor cyclic adenosine 3’,5’-monophosphate, PKA (protein kinase A)-dependent phosphorylation and cGMP (cyclic guanosine 3’,5’-monophosphate), we tested the hypothesis that dysregulation occurs in a sub-family of PDEs in the cytosol and outer mitochondrial membrane of neurons from the stellate ganglion. <br><strong> Results:<br></strong> PDE2A, 6D, 7A, 9A genes were highly expressed in young Wistar neurons and also conserved in neurons from spontaneously hypertensive rats (SHRs). In stellate neurons from prehypertensive SHRs, we found the levels of cyclic adenosine 3’,5’-monophosphate and cGMP at the outer mitochondrial membrane were decreased compared with normal neurons. The reduced cyclic adenosine 3’,5’-monophosphate response was due to the hydrolytic activity of overexpressed PDE2A2 located at the mitochondria. Normal cyclic adenosine 3’,5’-monophosphate levels were re-established by inhibition of PDE2A. There was also a greater PKA-dependent phosphorylation in the cytosol and at the outer mitochondrial membrane in spontaneously hypertensive rat neurons, where this response was regulated by protein phosphatases. The cGMP response was only restored by inhibition of PDE6. <br><strong> Conclusions:<br></strong> When taken together, these results suggest that site-specific inhibition of PDE2A and PDE6D at the outer mitochondrial membrane may provide a therapeutic target to ameliorate cardiac sympathetic impairment during the onset of hypertension.
spellingShingle Li, D
Liu, K
Davis, H
Robertson, C
Neely, OC
Tarafdar, A
Li, N
Lefkimmiatis, K
Zaccolo, M
Paterson, DJ
Abnormal cyclic nucleotide signaling at the outer mitochondrial membrane in sympathetic neurons during the early stages of hypertension
title Abnormal cyclic nucleotide signaling at the outer mitochondrial membrane in sympathetic neurons during the early stages of hypertension
title_full Abnormal cyclic nucleotide signaling at the outer mitochondrial membrane in sympathetic neurons during the early stages of hypertension
title_fullStr Abnormal cyclic nucleotide signaling at the outer mitochondrial membrane in sympathetic neurons during the early stages of hypertension
title_full_unstemmed Abnormal cyclic nucleotide signaling at the outer mitochondrial membrane in sympathetic neurons during the early stages of hypertension
title_short Abnormal cyclic nucleotide signaling at the outer mitochondrial membrane in sympathetic neurons during the early stages of hypertension
title_sort abnormal cyclic nucleotide signaling at the outer mitochondrial membrane in sympathetic neurons during the early stages of hypertension
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