Trypanosoma cruzi Infection Induces Pannexin-1 Channel Opening in Cardiac Myocytes

Abstract

, the etiological agent of Chagas diseases, invades the cardiac tissue causing acute myocarditis and heart electrical disturbances. In invasion, the parasite induces [Ca] transients in the host cells, an essential phenomenon for invasion. To date, knowledge on the mechanism that elicits transients of [Ca] during the infection of cardiac myocytes has not been fully characterized. Pannexin1 (Panx1) channel are poorly selective channels found in all vertebrates that serve as a pathway for ATP release. In this article, we demonstrate that infection results in the opening of Panx1 channels in cardiac myocytes. We show that pharmacological blockade of Panx1 channels inhibits-induced [Ca] transients and invasion in cardiac myocytes. Our results indicate that opening of Panx1 channels are required for invasion in cardiac myocytes, and we propose that targeting Panx1 channel could provide new potential therapeutic approaches to treat Chagas disease.

Possible Role of Gap Junction Channels and Non-Junctional Channels in the Infection Caused by Trypanosoma cruzi

“…Otherwise, the Panx1 channel is selective for chloride ions and exhibits no ATP permeability when stimulated simply by depolarization to positive potentials or the C-terminal is cleaved by proteolysis [38]. Since we found increased Panx1 channel activity and increase in ATP release in cells infected with T. cruzi [11], it suggested that under this condition the Panx1 channel does not undergo proteolysis and adopt the large channel configuration [11,38]. In addition, it has been described that Panx1-based channels are regulated by mechanical stress [39].…”

“…In 2018, we found that H510 strain of T. cruzi increased the Panx1 channel activity in rat neonatal cardiomyocytes at 1 hour postinfection [11]. Interestingly, the increased pannexon activity induced by the parasite was directly related to an elevated ATP release [11].…”

“…Interestingly, the increased pannexon activity induced by the parasite was directly related to an elevated ATP release [11]. This is relevant because ATP has been proposed as a key molecule in T. cruzi host cell invasion [11,50]. For example, blockade of P2Y 1 receptors with a MRS2179, a selective P2Y 1 antagonist, reduced T. cruzi-evoked Ca 2+ transients in rat cardiomyocytes [11].…”

“…This is relevant because ATP has been proposed as a key molecule in T. cruzi host cell invasion [11,50]. For example, blockade of P2Y 1 receptors with a MRS2179, a selective P2Y 1 antagonist, reduced T. cruzi-evoked Ca 2+ transients in rat cardiomyocytes [11]. Moreover, inhibition of mitochondrial ATP production by treating parasites with rotenone plus antimycin A reduced the infectivity of the parasites [50].…”

“…Interestingly, inhibitors of channels formed by proteins of the gap junction family such as suramin and boldine have trypanocidal activity and some of them are currently used for treatment of parasitic diseases such Human African Trypanosomiasis [2][3][4][5]. Also, studies have shown that infections caused by Trypanosoma cruzi (T. cruzi) modulate the expression of proteins of the gap junction family or modify the activity of the channels formed by these proteins in host cells [6][7][8][9][10][11]. Moreover, previous studies have shown gap junction type structures in Trypanosoma musculi [12].…”