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Ca(2+)-stimulated adenylyl cyclases (ACs) have recently been shown to play important roles in pacemaking in the sino-atrial node. Here we present evidence that Ca(2+)-stimulated ACs are functionally active in guinea-pig atrial myocytes. Basal activity of an AC in isolated atrial myocytes was demonstrated by the observations that MDL 12,330A (10 μm), an AC inhibitor, reduced L-type Ca(2+) current (I(CaL)) amplitude, while inhibition of phosphodiesterases with IBMX (100 μm) increased I(CaL) amplitude. Buffering of cytosolic Ca(2+) by exposure of myocytes to BAPTA-AM (5 μm) reduced I(CaL) amplitude, as did inhibition of Ca(2+) release from the sarcoplasmic reticulum with ryanodine (2 μm) and thapsigargin (1 μm). [Ca(2+)]i-activated calmodulin kinase II (CaMKII) inhibition with KN-93 (1 μm) reduced I(CaL), but subsequent application of BAPTA-AM further reduced I(CaL). This effect of BAPTA-AM, in the presence of CaMKII inhibition, demonstrates that there is an additional Ca(2+)-modulated pathway (not dependent on CaMKII) that regulates I(CaL) in atrial myocytes. The effects of BAPTA could be reversed by forskolin (10 μm), a direct stimulator of all AC isoforms, which would restore cAMP levels. In the presence of BAPTA-AM, the actions of IBMX were reduced. In addition, inclusion of cAMP in the patch electrode in the whole-cell configuration prevented the effects of BAPTA. These effects are all consistent with a role for Ca(2+)-stimulated AC in the regulation of atrial myocyte I(CaL).

Original publication

DOI

10.1113/jphysiol.2011.227066

Type

Journal article

Journal

J Physiol

Publication Date

15/04/2012

Volume

590

Pages

1881 - 1893

Keywords

Adenylyl Cyclases, Animals, Arteries, Calcium, Calcium Channels, L-Type, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cyclic AMP, Cytosol, Guinea Pigs, Heart Atria, Male, Myocytes, Cardiac, Phosphoric Diester Hydrolases, Ryanodine Receptor Calcium Release Channel, Sarcoplasmic Reticulum