Benzamil inhibits neuronal and heterologously expressed small conductance Ca2+-activated K+ channels

Castañeda, Marisol; Tonini, Raffaella; Richards, Christopher D.; Stocker, Martin; Pedarzani, Paola

doi:10.1016/j.neuropharm.2019.107738

Cited by 6 publications

(5 citation statements)

References 56 publications

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“…Ydegaard et al (2019) showed that acute administration of amiloride could still lower BP when eNOS was genetically deleted or preinhibited by L‐NAME in mice, indicating that the BP‐lowering effect is independent on EnNaC and eNOS, probably by inhibiting TRP channels and/or NCX, though the possibility that another compensatory mechanism was initiated when eNOS was inactivated cannot be ruled out. Benzamil, a more ENaC‐selective inhibitor, can also target other channels or transports, such as H + ‐K + ‐ATPases (Ayasse et al, 2021), NCX (Alves‐Lopes et al, 2020), small conductance Ca 2+ ‐activated K + channels (SK Ca ) (Castaneda et al, 2019), which is a component of EDHF (Edwards et al, 1998). Therefore, benzamil may target other channels to regulate vascular tone.…”

Section: Function Of Enac In Ecsmentioning

confidence: 99%

“…Importantly, amiloride was identified to inhibit the transient receptor potential (TRP) channels, including TRPA1 (Banke, 2011), and TRPC3 (Dai et al, 2007), and Na + /Ca 2+ exchanger (NCX) (Frelin et al, 1988) conductance Ca 2+ -activated K + channels (SK Ca ) (Castaneda et al, 2019), which is a component of EDHF (Edwards et al, 1998). Therefore, ben- this, it avoids the off-target effect of pharmacological inhibitors.…”

Section: Possible Reasons For the Discrepancymentioning

confidence: 99%

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Detrimental or beneficial: Role of endothelial ENaC in vascular function

Zhang

Yuan

Chen

et al. 2021

Journal Cellular Physiology

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In the past, it was believed that the expression of the epithelial sodium channel (ENaC) was restricted to epithelial tissues, such as the distal nephron, airway, sweat glands, and colon, where it is critical for sodium homeostasis. Over the past two decades, this paradigm has shifted due to the finding that ENaC is also expressed in various nonepithelial tissues, notably in vascular endothelial cells. In this review, the recent findings of the expression, regulation, and function of the endothelial ENaC (EnNaC) are discussed.The expression of EnNaC subunits is reported in a variety of endothelial cell lines and vasculatures, but this is controversial across different species and vessels and is not a universal finding in all vascular beds. The expression density of EnNaC is very faint compared to ENaC in the epithelium. To date, little is known about the regulatory mechanism of EnNaC. Through it can be regulated by aldosterone, the detailed downstream signaling remains elusive. EnNaC responds to increased extracellular sodium with the feedforward activation mechanism, which is quite different from the Na + self-inhibition mechanism of ENaC. Functionally, EnNaC was shown to be a determinant of cellular mechanics and vascular tone as it can sense shear stress, and its activation or insertion into plasma membrane causes endothelial stiffness and reduced nitric oxide production. However, in some blood vessels, EnNaC is essential for maintaining the integrity of endothelial barrier function. In this context, we discuss the possible reasons for the distinct role of EnNaC in vasculatures.

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Section: Function Of Enac In Ecsmentioning

confidence: 99%

Section: Possible Reasons For the Discrepancymentioning

confidence: 99%

Detrimental or beneficial: Role of endothelial ENaC in vascular function

Zhang

Yuan

Chen

et al. 2021

Journal Cellular Physiology

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“…Amiloride and its derivative Benzamil are high-affinity blockers of the epithelial Na + channel, ENaC, acting as a blocking agent of its pore ( Palmer and Andersen, 1989 ). Amiloride also functions as an inhibitor of several Na + transporters and nonselective cation channels, including Na + /Ca 2+ , and Na + /H + exchangers, nonselective cation channels, and voltage-gated K + and Ca 2+ channels ( Kleyman and Cragoe, 1988 ; Kleyman and Cragoe, 1990 ; Garcia et al, 1990 ; Sariban-Sohraby and Benos, 1986 ; Tytgat et al, 1990 ; Doi and Marunaka, 1995 ; Murata et al, 1995 ; Stoner and Viggiano, 2000 ; Hirsh, 2002 ; Castañeda et al, 2019 ), including PC2 ( González-Perrett et al, 2001 ), and PC2-like (TRPP3) channel ( Dai et al, 2007 ). The treatment with amiloride at a concentration expected to produce a complete inhibition of the PC2 channel (200 μM, González-Perrett et al, 2001 ) produced an increase in ciliary length, although it is possible for amiloride to block other Ca 2+ entry mechanisms or channels such as ciliary ENaC ( Raychowdhury et al, 2005 ) that may affect ciliary length independently.…”

Section: Discussionmentioning

confidence: 99%

Polycystin-2 (TRPP2) regulates primary cilium length in LLC-PK1 renal epithelial cells

et al. 2022

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Polycystin-2 (PC2, TRPP2) is a Ca2+ permeable nonselective cation channel whose dysfunction generates autosomal dominant polycystic kidney disease (ADPKD). PC2 is present in different cell locations, including the primary cilium of renal epithelial cells. However, little is known as to whether PC2 contributes to the primary cilium structure. Here, we explored the effect(s) of external Ca2+, PC2 channel blockers, and PKD2 gene silencing on the length of primary cilia in wild-type LLC-PK1 renal epithelial cells. Confluent cell monolayers were fixed and immuno-labeled with an anti-acetylated α-tubulin antibody to identify primary cilia and measure their length. Although primary cilia length measurements did not follow a Normal distribution, the data were normalized by Box-Cox transformation rendering statistical differences under all experimental conditions. Cells exposed to high external Ca2+ (6.2 mM) decreased a 13.5% (p < 0.001) primary cilia length as compared to controls (1.2 mM Ca2+). In contrast, the PC2 inhibitors amiloride (200 μM) and LiCl (10 mM), both increased primary ciliary length by 33.2% (p < 0.001), and 17.4% (p < 0.001), respectively. PKD2 gene silencing by siRNA elicited a statistically significant, 10.3% (p < 0.001) increase in primary cilia length compared to their respective scrambled RNA transfected cells. The data indicate that conditions that regulate PC2 function or gene expression modify the length of primary cilia in renal epithelial cells. Blocking of PC2 mitigates the effects of elevated external Ca2+ concentration on primary cilia length. Proper regulation of PC2 function in the primary cilium may be essential in the onset of mechanisms that trigger cyst formation in ADPKD.

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“…The reason for the differences in resistance seen in cdh23 mutants vs. benzamil treatment may be that unlike cdh23, benzamil is likely not blocking mechanotransduction selectively. Amiloride and benzamil are both considered nonselective epithelial sodium channel blockers and have been shown to be capable of blocking a number of channel types including some Ca 2+ , TRP, and K + channels (Bielefeld et al, 1986;Tang et al, 1988;Dai et al, 2007;Castañeda et al, 2019). Therefore, while the mechanotransduction channel may serve as a major entry route for cadmium, cadmium could also be entering at a lower level through other channel types blocked by benzamil, thus allowing for the low level of hair cell death seen in cdh23 mutants.…”

Section: Discussionmentioning

confidence: 99%

Mechanotransduction Activity Facilitates Hair Cell Toxicity Caused by the Heavy Metal Cadmium

Schmid

Alampi

Briggs

et al. 2020

Front. Cell. Neurosci.

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Hair cells are sensitive to many insults including environmental toxins such as heavy metals. We show here that cadmium can consistently kill hair cells of the zebrafish lateral line. Disrupting hair cell mechanotransduction genetically or pharmacologically significantly reduces the amount of hair cell death seen in response to cadmium, suggesting a role for mechanotransduction in this cell death process, possibly as a means for cadmium uptake into the cells. Likewise, when looking at multiple cilia-associated gene mutants that have previously been shown to be resistant to aminoglycoside-induced hair cell death, resistance to cadmium-induced hair cell death is only seen in those with mechanotransduction defects. In contrast to what was seen with mechanotransduction, significant protection was not consistently seen from other ions previously shown to compete for cadmium uptake into cells or tissue including zinc and copper. These results show that functional mechanotransduction activity is playing a significant role in cadmium-induced hair cell death.

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Benzamil inhibits neuronal and heterologously expressed small conductance Ca2+-activated K+ channels

Cited by 6 publications

References 56 publications

Detrimental or beneficial: Role of endothelial ENaC in vascular function

Detrimental or beneficial: Role of endothelial ENaC in vascular function

Polycystin-2 (TRPP2) regulates primary cilium length in LLC-PK1 renal epithelial cells

Mechanotransduction Activity Facilitates Hair Cell Toxicity Caused by the Heavy Metal Cadmium

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