Extracellular UTP stimulates electrogenic bicarbonate secretion across CFTR knockout gallbladder epithelium

Area of Science:

• Physiology
• Gastroenterology
• Cell Biology

Background:

• Cystic fibrosis (CF) involves impaired CFTR-mediated secretion, leading to pancreatic and biliary issues.
• P2Y(2) receptor agonists are explored to bypass CFTR defects by stimulating chloride secretion.
• The effect of these agonists on bicarbonate secretion in CF remains unclear.

Purpose of the Study:

• To investigate the role of P2Y(2) receptor agonists in stimulating transepithelial bicarbonate secretion.
• To determine the mechanism of anion conductance activated by P2Y(2) receptors in CF gallbladder.

Main Methods:

• Ussing chamber studies on gallbladder mucosa from CFTR knockout mice.
• Activation of luminal P2Y(2) receptors using UTP.
• Measurement of short-circuit current (I(sc)) and bicarbonate flux (J(s-->m)) under various ionic conditions and with inhibitors (DIDS, bumetanide).

Main Results:

• UTP induced a sustained, Cl(-) independent, HCO(3)(-) dependent plateau in I(sc).
• UTP increased both I(sc) and HCO(3)(-) secretion (J(s-->m)) in pH stat studies.
• The UTP-induced response was insensitive to bumetanide but blocked by luminal DIDS, indicating Ca(2+)-dependent anion conductance.

Conclusions:

• P2Y(2) receptor activation stimulates electrogenic bicarbonate secretion in CF gallbladder.
• This secretion is mediated by an intracellular Ca(2+)-dependent anion conductance, independent of CFTR.
• P2Y(2) agonists represent a potential therapeutic avenue for CF-related digestive diseases.