▲ FIGURE 13-20 Localization of protein kinase A (PKA) to the nuclear membrane in heart muscle. This A kinase-associated protein mAKAP anchors both PKA and cAMP phosphodiesterase (PDE) to the nuclear membrane, maintaining them in a negative feedback loop that provides close local control of the cAMP level. Step 1: The basal level of PDE activity in the absence of hormone (resting state) keeps cAMP levels below those necessary for PKA activation. Step |2|: Activation of p-adrenergic receptors causes an increase in cAMP level in

4| Return to resting state excess of that which can be degraded by PDE. The resulting binding of cAMP to the regulatory (R) subunits of PKA releases the active catalytic (C) subunits. Step |3|: Subsequent phosphorylation of PDE by PKA stimulates its catalytic activity, thereby driving cAMP levels back to basal and causing reformation of the inactive PKA. Subsequent dephosphorylation of PDE (step |4|) returns the complex to the resting state. [Adapted from K. L. Dodge et al., 2001, EMBO J. 20:1921.]

close local control of the cAMP level and hence PKA activity (Figure 13-20). The localization of PKA near the nuclear membrane also facilitates entry of the catalytic subunits into the nucleus, where they phosphorylate and activate certain transcription factors (Section 13.6).

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