A second hypothesis for bestrophin function is that this family of proteins functions as regulators of ion transport.
5 6 9 10 11 We have shown that L-type voltage dependent Ca
2+ channels (VDCCs) are required for the light peak,
9 11 20 and that Best1 and Best1 mutants exert specific effects on the kinetics of VDCCs,
9 11 a finding recently confirmed by Yu et al.,
10 who also demonstrated a physical interaction of Best1 with the β3 subunit of VDCC channels. Thus, Best2 may play a role in regulating Ca
2+ signaling, similar to what we have proposed for Best1.
5 9 11 The NPE is in close physical contact with the pigment epithelium (PE), working in tandem to generate the aqueous flow. According to Mitchell et al.
21 PE cells release ATP due to cell swelling, which results in activation of a hypothesized Ca
2+ dependent negative feedback loop sending Cl
− into the stroma.
2 21 ATP stimulates P2Y2 receptors in PE cells to trigger Ca
2+ release. In mice, disruption of Best1 results in an increase in [Ca
2+]
i compared with wild-type mice in response to extracellular ATP, suggesting that Best1 functions to regulate intracellular Ca
2+ signaling. Although Best2 is in the NPE and not the PE, these cells communicate through an extensive network of GAP junctions.
22 Perhaps, Best2 normally acts as the governor of the negative feedback loop altering Ca
2+ signaling to promote aqueous resorption to control the desired rate of aqueous flow. In its absence this failure to properly regulate Ca
2+ signaling could result in a diminished rate of Cl
− recycling and thus enhanced aqueous production.