Title

Adenylate Cyclase 1 Links Calcium Signaling to CFTR-Dependent Cytosolic Chloride Elevations in Chick Amacrine Cells

Document Type

Article

Publication Date

1-1-2021

Abstract

The strength and sign of synapses involving ionotropic GABA and glycine receptors are dependent upon the Cl gradient. We have shown that nitric oxide (NO) elicits the release of Cl from internal acidic stores in retinal amacrine cells (ACs); temporarily altering the Cl gradient and the strength or even sign of incoming GABAergic or glycinergic synapses. The underlying mechanism for this effect of NO requires the cystic fibrosis transmembrane regulator (CFTR) but the link between NO and CFTR activation has not been determined. Here, we test the hypothesis that NO-dependent Ca elevations activate the Ca-dependent adenylate cyclase 1 (AdC1) leading to activation of protein kinase A (PKA) whose activity is known to open the CFTR channel. Using the reversal potential of GABA-gated currents to monitor cytosolic Cl, we established the requirement for Ca elevations. Inhibitors of AdC1 suppressed the NO-dependent increases in cytosolic Cl whereas inhibitors of other AdC subtypes were ineffective suggesting that AdC1 is involved. Inhibition of PKA also suppressed the action of NO. To address the sufficiency of this pathway in linking NO to elevations in cytosolic Cl, GABA-gated currents were measured under internal and external zero Cl conditions to isolate the internal Cl store. Activators of the cAMP pathway were less effective than NO in producing GABA-gated currents. However, coupling the cAMP pathway activators with the release of Ca from stores produced GABA-gated currents indistinguishable from those stimulated with NO. Together, these results demonstrate that cytosolic Ca links NO to the activation of CFTR and the elevation of cytosolic Cl.

Publication Source (Journal or Book title)

Frontiers in cellular neuroscience

First Page

726605

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