Biased PKIα expression may reduce nuclear PKA sensitivity to ISO stimulation. A, Simulated AKAR-NLS responses to 1 μmol/L ISO with increasing nuclear phosphatase expression. B, Model predicts nuclear phosphatase inhibition does not recover AKAR-NLS’s ISO sensitivity. C, Experimental validation for model simulations. Pre-treatment with 10 nmol/L Calyculin A does not alter nuclear AKAR-NLS sensitivity to ISO (n ≥ 9 cells each). D, Model predicts nuclear PKA ISO sensitivity requires biased PKI expression. E, Immunofluorescence labeling with anti-PKIα antibodies identify nearly exclusive nuclear PKIα expression.