AKAP79/150 Signal Complexes in G-Protein Modulation of Neuronal Ion Channels

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Abstract
Voltage-gated M-type (KCNQ) K+channels play critical roles in regulation of neuronal excitability. Previous work showed A-kinase-anchoring protein (AKAP)79/150-mediated protein kinase C (PKC) phosphorylation of M channels to be involved in M current (IM) suppression by muscarinic M1, but not bradykinin B2, receptors. In this study, we first explored whether purinergic and angiotensin suppression ofIMin superior cervical ganglion (SCG) sympathetic neurons involves AKAP79/150. Transfection into rat SCG neurons of ΔA-AKAP79, which lacks the A domain necessary for PKC binding, or the absence of AKAP150 inAKAP150−/−mice, did not affectIMsuppression by purinergic agonist or by bradykinin, but reducedIMsuppression by muscarinic agonist and angiotensin II. Transfection of AKAP79, but not ΔA-AKAP79 or AKAP15, rescued suppression ofIMby muscarinic receptors inAKAP150−/−neurons. We also tested association of AKAP79 with M1, B2, P2Y6, and AT1receptors, and KCNQ2 and KCNQ3 channels, via Förster resonance energy transfer (FRET) on Chinese hamster ovary cells under total internal refection fluorescence microscopy, which revealed substantial FRET between AKAP79 and M1or AT1receptors, and with the channels, but only weak FRET with P2Y6or B2receptors. The involvement of AKAP79/150 in Gq/11-coupled muscarinic regulation of N- and L-type Ca2+channels and by cAMP/protein kinase A was also studied. We found AKAP79/150 to not play a role in the former, but to be necessary for forskolin-induced upregulation of L-current. Thus, AKAP79/150 action correlates with the PIP2(phosphatidylinositol 4,5-bisphosphate)-depletion mode ofIMsuppression, but does not generalize to Gq/11-mediated inhibition of N- or L-type Ca2+channels.

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