Evidence that 5‐HT stimulates intracellular Ca<sup>2+</sup> signalling and activates pannexin‐1 currents in type II cells of the rat carotid body

Murali, Sindhubarathi; Zhang, Min; Nurse, Colin A.

doi:10.1113/jp273473

Cited by 17 publications

(49 citation statements)

References 43 publications

(127 reference statements)

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“…Similar to previous studies (Murali et al, 2017), 5-HT (5 M) caused a delayed activation of an inward Panx-1-like current at a holding potential of −60 mV in several type II cells, as exemplified in Figure 1a.…”

Section: Role Of Src Family Kinase In the Activation Of The Pannexin-supporting

confidence: 88%

“…Previous studies from this laboratory demonstrated that 5-HT acts on ketanserin-sensitive 5-HT2Rs on type II cells leading to an increase in intracellular Ca 2+ that appears necessary for the activation of ATP-permeable Panx-1 channels (Murali et al, 2017). SFK, PKA and PKC, in the 5-HT-5HT2R signalling pathway in type II glial cells of the rat CB.…”

Section: Discussionmentioning

confidence: 87%

“…Furthermore, given that the 5-HT receptors on type II cells can be activated by low, submicromolar concentrations of 5-HT (EC 50 ∼200 nM) (Murali et al, 2017), this glial pathway might also be involved in other pathological situations, e.g. obesity and insulin resistance, where circulating concentrations of 5-HT are elevated (Crane et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…In previous studies, the 5-HT-activated inward current in type II cells was reversibly inhibited by the 5-HT2R blocker, ketanserin (Murali et al, 2017). Given that 5-HT2Rs typically couple to PKC signalling via the G q-Phospholipase C (PLC)-IP 3 pathway, we next tested the effects of PKC inhibition.…”

Section: Contrasting Roles Of Pka and Pkc In 5-ht-versus Utp-induced mentioning

confidence: 99%

“…low doses of carbenoxolone (5 M) or by 10 Panx mimetic peptide (Murali et al, 2014(Murali et al, , 2015(Murali et al, , 2017Zhang et al, 2012); (ii) Panx-1 immunoreactivity has been detected in Glial fibrillary acidic protein (GFAP)-positive type II cells in dissociated CB cell cultures or tissue sections of rat CB in situ (Zhang et al, 2012); and (iii) stimulated type II cells release ATP via carbenoxonlone-sensitive channels when situated near P2X2/3expressing petrosal neurons as biosensors (Zhang et al, 2012) or near type I cells that respond to adenosine derived from ATP breakdown by ectonucleotidases (Murali & Nurse, 2016). low doses of carbenoxolone (5 M) or by 10 Panx mimetic peptide (Murali et al, 2014(Murali et al, , 2015(Murali et al, , 2017Zhang et al, 2012); (ii) Panx-1 immunoreactivity has been detected in Glial fibrillary acidic protein (GFAP)-positive type II cells in dissociated CB cell cultures or tissue sections of rat CB in situ (Zhang et al, 2012); and (iii) stimulated type II cells release ATP via carbenoxonlone-sensitive channels when situated near P2X2/3expressing petrosal neurons as biosensors (Zhang et al, 2012) or near type I cells that respond to adenosine derived from ATP breakdown by ectonucleotidases (Murali & Nurse, 2016).…”

Section: Significance Of the Present Findings For The Role Of Phosphomentioning

confidence: 99%

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Evidence for protein kinase involvement in the 5‐HT–[Ca²⁺]_i–pannexin‐1 signalling pathway in type II glial cells of the rat carotid body

Leonard

Zhang

Nurse

2018

Experimental Physiology

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New Findings What is the central question of this study?The mammalian carotid body (CB) is a peripheral chemoreceptor organ involved in O2 and CO2/H+ homeostasis. Recent studies suggest that 5‐HT, released from CB receptor cells, can stimulate adjacent glial‐like type II cells, leading to an increase in intracellular Ca2+ (Δ[Ca2+]i) and activation of ATP‐permeable pannexin‐1 (Panx‐1) channels. The aim of this study was to elucidate the role of protein kinases in the 5‐HT–[Ca2+]i–Panx‐1 signalling pathway. What is the main finding and its importance?Src family kinase and protein kinase A, acting downstream from Δ[Ca2+]i, played central roles in 5‐HT‐mediated Panx‐1 channel activation. This provides new insight into mechanisms regulating CB excitation, especially in pathophysiological conditions. Abstract Chemoreceptor (type I) cells of the rodent carotid body (CB) synthesize and release several neurotransmitters/neuromodulators, including 5‐hydroxytryptamine (5‐HT), implicated in enhanced CB excitation after exposure to chronic intermittent hypoxia, e.g. sleep apnoea. However, recent studies suggest that 5‐HT can robustly stimulate adjacent glial‐like type II cells via ketanserin‐sensitive 5‐HT2 receptors, leading to intracellular Ca2+ elevation (Δ[Ca2+]i) and activation of ATP‐permeable pannexin‐1 (Panx‐1) channels. Using dissociated rat CB cultures, we investigated the role of protein kinases in the intracellular signalling pathways in type II cells. In isolated type II cells, 5‐HT activated a Panx‐1‐like inward current (I5‐HT) that was reversibly inhibited by the Src family kinase inhibitor PP2 (1 μm), but not by its inactive analogue, PP3 (1 μm). Moreover, I5‐HT was reversibly inhibited (>90%) by H89 (1 μm), a protein kinase A blocker, whereas the protein kinase C blocker GF109203X (2 μm) was largely ineffective. In contrast, the P2Y2R agonist UTP (100 μm) activated Panx‐1‐like currents that were reversibly inhibited (∼60%) by either H89 or GF109203X. Using fura‐2 spectrofluorimetry, the 5‐HT‐induced Δ[Ca2+]i was unaffected by PP2, H89 and GF109293X, suggesting that the kinases acted downstream of the Ca2+ rise. Given that intracellular Ca2+ chelation was previously shown to block receptor‐mediated Panx‐1 current activation in type II cells, these data suggest that CB neuromodulators use overlapping, but not necessarily identical, signalling pathways to activate Panx‐1 channels and release ATP, a CB excitatory neurotransmitter. In conclusion, these studies provide new mechanistic insight into 5‐HT signalling in the CB that has pathophysiological relevance.

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Section: Role Of Src Family Kinase In the Activation Of The Pannexin-supporting

confidence: 88%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Contrasting Roles Of Pka and Pkc In 5-ht-versus Utp-induced mentioning

confidence: 99%

Section: Significance Of the Present Findings For The Role Of Phosphomentioning

confidence: 99%

See 3 more Smart Citations

Evidence for protein kinase involvement in the 5‐HT–[Ca²⁺]_i–pannexin‐1 signalling pathway in type II glial cells of the rat carotid body

Leonard

Zhang

Nurse

2018

Experimental Physiology

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The Carotid Body “Tripartite Synapse”: Role of Gliotransmission

Leonard

Nurse

2023

Advances in Experimental Medicine and Biology

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Pannexin 1 channels in renin-expressing cells influence renin secretion and blood pressure homeostasis

DeLalio

Masati

Mendu

et al. 2020

Kidney International

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Kidney function and blood pressure homeostasis are regulated by purinergic signaling mechanisms. These autocrine/paracrine signaling pathways are initiated by the release of cellular ATP, which influences kidney hemodynamics and steady-state renin secretion from juxtaglomerular cells. However, the mechanism responsible for ATP release that supports tonic inputs to juxtaglomerular cells and regulates renin secretion remains unclear. Pannexin 1 (Panx1) channels localize to both afferent arterioles and juxtaglomerular cells and provide a transmembrane conduit for ATP release and ion permeability in the kidney and the vasculature. We hypothesized that Panx1 channels in renin-expressing cells regulate renin secretion in vivo. Using a renin cell-specific Panx1 knockout model, we found that male Panx1 deficient mice exhibiting a heightened activation of the reninangiotensin-aldosterone system have markedly increased plasma renin and aldosterone concentrations, and elevated mean arterial pressure with altered peripheral hemodynamics. Following ovariectomy, female mice mirrored the male phenotype. Furthermore, constitutive Panx1 channel activity was observed in As4.1 reninsecreting cells, whereby Panx1 knockdown reduced extracellular ATP accumulation, lowered basal intracellular calcium concentrations and recapitulated a hyper-secretory renin phenotype. Moreover, in response to stress stimuli that lower blood pressure, Panx1-deficient mice exhibited aberrant "renin recruitment" as evidenced by reactivation of renin expression in pre-glomerular arteriolar smooth muscle cells. Thus, renin-cell Panx1 channels suppress renin secretion and influence adaptive renin responses when blood pressure homeostasis is threatened.

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Evidence that 5‐HT stimulates intracellular Ca²⁺ signalling and activates pannexin‐1 currents in type II cells of the rat carotid body

Cited by 17 publications

References 43 publications

Evidence for protein kinase involvement in the 5‐HT–[Ca²⁺]_i–pannexin‐1 signalling pathway in type II glial cells of the rat carotid body

Evidence for protein kinase involvement in the 5‐HT–[Ca²⁺]_i–pannexin‐1 signalling pathway in type II glial cells of the rat carotid body

The Carotid Body “Tripartite Synapse”: Role of Gliotransmission

Pannexin 1 channels in renin-expressing cells influence renin secretion and blood pressure homeostasis

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Evidence that 5‐HT stimulates intracellular Ca2+ signalling and activates pannexin‐1 currents in type II cells of the rat carotid body

Cited by 17 publications

References 43 publications

Evidence for protein kinase involvement in the 5‐HT–[Ca2+]i–pannexin‐1 signalling pathway in type II glial cells of the rat carotid body

Evidence for protein kinase involvement in the 5‐HT–[Ca2+]i–pannexin‐1 signalling pathway in type II glial cells of the rat carotid body

The Carotid Body “Tripartite Synapse”: Role of Gliotransmission

Pannexin 1 channels in renin-expressing cells influence renin secretion and blood pressure homeostasis

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Product

Resources

About

Evidence that 5‐HT stimulates intracellular Ca²⁺ signalling and activates pannexin‐1 currents in type II cells of the rat carotid body

Evidence for protein kinase involvement in the 5‐HT–[Ca²⁺]_i–pannexin‐1 signalling pathway in type II glial cells of the rat carotid body

Evidence for protein kinase involvement in the 5‐HT–[Ca²⁺]_i–pannexin‐1 signalling pathway in type II glial cells of the rat carotid body