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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Inhibition of serine/threonine phosphatase enhances arachidonic acid-induced [Ca²⁺]_i via protein kinase A

Departments of ¹Oral Biology and ²Pharmacology, University of Washington, Seattle, Washington

Submitted 30 May 2008 ; accepted in final form 3 November 2008

Arachidonic acid (AA) regulates intracellular calcium concentration ([Ca²⁺]_i) in a variety of cell types including salivary cells. In the present study, the effects of serine/threonine phosphatases on AA-induced Ca²⁺ signaling in mouse parotid acini were determined. Mice were euthanized with CO₂. Treatment of acini with the serine/threonine phosphatase inhibitor calyculin A blocked both thapsigargin- and carbachol-induced Ca²⁺ entry but resulted in an enhancement of AA-induced Ca²⁺ release and entry. Effects were mimicked by the protein phosphatase-1 (PP1) inhibitor tautomycin but were inhibited by the PP2A inhibitor okadaic acid. The protein kinase A (PKA) inhibitor PKI_(14-22) significantly attenuated AA-induced enhancement of Ca²⁺ release and entry in the presence of calyculin A, whereas it had no effect on calyculin A-induced inhibition of thapsigargin-induced Ca²⁺ responses. The ryanodine receptor (RyR) inhibitor, tetracaine, and StHt-31, a peptide known to competitively inhibit type II PKA regulatory subunit binding to PKA-anchoring protein (AKAP), abolished calyculin A enhancement of AA-induced Ca²⁺ release and entry. StHt-31 also abolished forskolin potentiation of 4-chloro-3-ethylphenol (4-CEP) and AA on Ca²⁺ release but had no effect on 8-(4-methoxyphenylthio)-2'-O-methyladenosine-3',5'-cAMP potentiation of 4-CEP responses. Results suggest that inhibition of PP1 results in an enhancement of AA-induced [Ca²⁺]_i via PKA, AKAP, and RyRs.

calyculin A; protein kinase A-anchoring protein; ryanodine receptor; StHt-31; 8-(4-methoxyphenylthio)-2'-O-methyladenosine-3',5'-cAMP