Ganglionic GFAP+ glial Gq-GPCR signaling enhances heart functions in vivo

Xie, Alison Xiaoqiao; Lee, Jakovin J; McCarthy, Ken D.

doi:10.1172/jci.insight.90565

Cited by 32 publications

(44 citation statements)

References 107 publications

(119 reference statements)

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“…In our study, we also found that chronic activation of satellite glial Gq-GPCR signaling led to significant decreases in blood pressure in female GFAP-hM3Dq mice, suggesting a strong link between sympathetic SGC Gq-GPCR signaling and blood pressure regulation [14] . However, can we manipulate Gq-GPCR signaling exclusively in sympathetic SGCs in vivo?…”

Section: Can We Target Sgc Signaling In the Sympathetic Ganglia For Tsupporting

confidence: 72%

“…hM3Dq does not exhibit intrinsic activity in the absence of CNO [19] ; thus, there are no baseline differences in physiology or behavior between GFAP-hM3Dq mice and wild-type littermate controls [13] . In contrast, a single Intraperitoneal injection (i. p.) of CNO leads to significant increases in both heart rate and left ventricle contraction in GFAP-hM3Dq mice [14,15] . Using the GFAP-hM3Dq transgenic model, we provided clear pharmacological evidence supporting that peripheral GFAP + glia, specifically satellite glial cells (SGCs) in the sympathetic ganglia, positively modulate sympathetic released norepinephrine (NE) onto the heart, and in turn significantly increases cardiac contractility [14] .…”

Section: A Pharmacogenetic Model For Studying Gq-gpcr Activation In Gmentioning

confidence: 94%

“…In order to selectively activate Gq-GPCR signaling pathway in GFAP + glia without activating other cells types, we took advantage of the newly developed Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) [13,14] . DREADDs are engineered by introducing point-mutations to endogenous muscarinic receptors (mAChR) [15] .…”

Section: A Pharmacogenetic Model For Studying Gq-gpcr Activation In Gmentioning

confidence: 99%

“…Venoconstriction also contributes to increased cardiac preload. SPGN: spinal pre-ganglionic neurons; PGN: post-ganglionic neurons; EPI: epinephrine; NE: norepinephrine organs, including the heart and blood vessels [13][14][15] . CNO can cross the blood brain barrier (BBB), making the GFAP-hM3Dq transgenic mice a unique model for assessing the role of Gq-GPCR activation in GFAP + glia in vivo [16,17] .…”

Section: A Pharmacogenetic Model For Studying Gq-gpcr Activation In Gmentioning

confidence: 99%

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Targeting sympathetic glia for treating cardiovascular diseases

Xie

Chaia

McCarthy³

2017

Receptor Clin Invest

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Gq G protein-coupled receptor (Gq-GPCR) signaling in glial fibrillary acidic protein-expressing (GFAP + ) glia is essential for neuron-glia interaction in the Central Nervous System (CNS). However, the exploration of the roles of Gq-GPCR signaling in peripheral GFAP + glia has just begun. Our recent study showed that GFAP + glia in the sympathetic ganglia, namely satellite glial cells (SGCs), positively modulate sympathetic-regulated cardiac functions following their Gq-GPCR activation. In this research highlight, we discuss the significance of satellite glial modulation of sympathetic nerve activity (SNA) in both physiology and in diseases. We also present a new experimental strategy for manipulating satellite glial signaling in the sympathetic ganglia using adeno-associated virus (AAV). The success of targeted viral transduction in ganglionic SGCs suggest a strong therapeutic potential of targeting sympathetic glia for the treatment of cardiovascular diseases (CVDs).

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Section: Can We Target Sgc Signaling In the Sympathetic Ganglia For Tsupporting

confidence: 72%

Section: A Pharmacogenetic Model For Studying Gq-gpcr Activation In Gmentioning

confidence: 94%

Section: A Pharmacogenetic Model For Studying Gq-gpcr Activation In Gmentioning

confidence: 99%

Section: A Pharmacogenetic Model For Studying Gq-gpcr Activation In Gmentioning

confidence: 99%

See 2 more Smart Citations

Targeting sympathetic glia for treating cardiovascular diseases

Xie

Chaia

McCarthy³

2017

Receptor Clin Invest

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“…Recent studies using genetic manipulations of sympathetic satellite glia have implicated these cells in the regulation of target organ function by demonstrating that selective activation of Gq-GPCR (G protein-coupled receptor) signaling in peripheral glia leads to the modulation of cardiac properties in adult mice [27, 28]. These effects are mediated through postganglionic sympathetic innervation of the heart raising the possibility that activated glia influence the active properties of sympathetic neurons within the ganglia.…”

Section: Introductionmentioning

confidence: 99%

Satellite glial cells modulate cholinergic transmission between sympathetic neurons

Enes

Sona

Gerard

et al. 2019

Preprint

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Satellite glial regulation of sympathetic activity" 15 16 17 18 40 Introduction 41 Glial cells, once thought of as neuron support cells, are now recognized as 42 active players in the formation and function of normal brain circuitry [1, 2]. 43 Astrocytes, the most abundant glial cell type in the brain, regulate many properties 44 of neuronal circuits such as neuronal excitability, synaptic transmission and 45 plasticity [3-5]. Their role at central nervous system (CNS) synapses has been the 46 focus of a number of studies in the past two decades, showing that astrocytes control 47 4 61 under pathological conditions such as hypertension and chronic heart disease [20, 62 21]. Sympathetic tone is initially set by neurons present in the brain and spinal cord 63 [22], with the sympathetic ganglionic neurons acting as the final regulatory element 64 determining the output of the sympathetic circuit. 65 A striking anatomical feature of the sympathetic ganglion is the presence of 66 satellite glia that form an envelope around individual ganglionic neuronal somata 67 and cover synapses [23]. This is in contrast to the CNS where individual astrocytes 68 are in contact with multiple neurons [24]. While the function of the satellite glia 69 remains to be fully defined, both sympathetic and sensory satellite glia share several 70 cellular and molecular features with astrocytes, including expression of 71 neurotransmitter receptors and the formation of a glia network via gap junctions 72 [25]. Satellite glia injury responses are characterized by changes in expression 73 profiles, including an up-regulation of the activation marker glial fibrillary acidic 74 protein (GFAP) [26]. These findings point to a possible effect in disease progression 75 and suggest that satellite glia play roles in both normal function and disease in the 76 peripheral nervous system. 77 Recent studies using genetic manipulations of sympathetic satellite glia have 78 implicated these cells in the regulation of target organ function by demonstrating 79 that selective activation of Gq-GPCR (G protein-coupled receptor) signaling in 80 peripheral glia leads to the modulation of cardiac properties in adult mice [27, 28]. 81 These effects are mediated through postganglionic sympathetic innervation of the 82 heart raising the possibility that activated glia influence the active properties of 157 in 4% paraformaldehyde (PFA) and then cryo-protected by incubating them in 30%

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Single‐cell transcriptomic profiling of satellite glial cells in stellate ganglia reveals developmental and functional axial dynamics

Weperen

Littman²,

Arneson

et al. 2021

Glia

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Stellate ganglion neurons, important mediators of cardiopulmonary neurotransmission, are surrounded by satellite glial cells (SGCs), which are essential for the function, maintenance, and development of neurons. However, it remains unknown whether SGCs in adult sympathetic ganglia exhibit any functional diversity, and what role this plays in modulating neurotransmission. We performed single‐cell RNA sequencing of mouse stellate ganglia (n = 8 animals), focusing on SGCs (n = 11,595 cells). SGCs were identified by high expression of glial‐specific transcripts, S100b and Fabp7. Microglia and Schwann cells were identified by expression of C1qa/C1qb/C1qc and Ncmap/Drp2, respectively, and excluded from further analysis. Dimensionality reduction and clustering of SGCs revealed six distinct transcriptomic subtypes, one of which was characterized the expression of pro‐inflammatory markers and excluded from further analyses. The transcriptomic profiles and corresponding biochemical pathways of the remaining subtypes were analyzed and compared with published astrocytic transcriptomes. This revealed gradual shifts of developmental and functional pathways across the subtypes, originating from an immature and pluripotent subpopulation into two mature populations of SGCs, characterized by upregulated functional pathways such as cholesterol metabolism. As SGCs aged, these functional pathways were downregulated while genes and pathways associated with cellular stress responses were upregulated. These findings were confirmed and furthered by an unbiased pseudo‐time analysis, which revealed two distinct trajectories involving the five subtypes that were studied. These findings demonstrate that SGCs in mouse stellate ganglia exhibit transcriptomic heterogeneity along maturation or differentiation axes. These subpopulations and their unique biochemical properties suggest dynamic physiological adaptations that modulate neuronal function.

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Ganglionic GFAP+ glial Gq-GPCR signaling enhances heart functions in vivo

Cited by 32 publications

References 107 publications

Targeting sympathetic glia for treating cardiovascular diseases

Targeting sympathetic glia for treating cardiovascular diseases

Satellite glial cells modulate cholinergic transmission between sympathetic neurons

Single‐cell transcriptomic profiling of satellite glial cells in stellate ganglia reveals developmental and functional axial dynamics

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