Mibefradil, a T-type Ca channel blocker also blocks Orai channels by action at the extracellular surface.

Background And Purpose: Mibefradil, a T-type Ca channel blocker, has been investigated for treating solid tumours. However, its underlying mechanisms are still unclear. Here, we have investigated the pharmacological actions of mibefradil on Orai store-operated Ca channels.

ORAI channels are critical for receptor-mediated endocytosis of albumin.

Impaired albumin reabsorption by proximal tubular epithelial cells (PTECs) has been highlighted in diabetic nephropathy (DN), but little is known about the underlying molecular mechanisms. Here we find that ORAI1-3, are preferentially expressed in PTECs and downregulated in patients with DN. Hyperglycemia or blockade of insulin signaling reduces the expression of ORAI1-3.