Протеинкиназа а

The features of the tmAC molecule in the left panel are highlighted in the text. ER vesicles containing tmAC and ryanodine activated channels: note that co-localization in the same vesicle is not a criterion of the hypothesis: AC sensing of local Ca2+ release and PKA activation by cAMP produced from the juxtaposed AC is sufficient. An increase of intracellular Ca2+ triggered, for example, by Ca2+ conducting NMDA or AMPA receptors could initiate self-propagating cAMP gradients along the dendritic tree. This could be amplified by ligands of Gs coupled 7-TM. The propagated cAMP signal eventually reaches the cell body to alter gene expression or influence the state of phosphorylation of proteins at the axon initial segment.

The molecular topography of tmAC makes it likely that it is active in intracellular vesicles – implications of a case study of Ca2+/calmodulin stimulated tmACs (AC1 and AC8) are shown.

B, Yotiao binds to AC2, in addition to AC 1, 3, and 9. The anchoring of a PKA-regulated PDE sets up potential feedback regulation of cAMP levels independent of Yotiao-mediated inhibition of AC2.

C, mAKAPβ complexes assembled on the nuclear envelope. In this model, βAR-stimulated AC5 increases cAMP to activate anchored PKA and potentially EPAC. PKA phosphorylation of the ryanodine receptor (RyR) increases channel activity to allow for Ca²⁺ activation of CaN. Several feedback loops are also initiated, including PKA-dependent inhibition of AC5 to decrease cAMP synthesis and activation of PDE4D3 by PKA to increase cAMP breakdown. The binding of ERK1/2 to PDE4D3 is not shown.

Structure of the catalytic C1 and C2 domains of mammalian membrane-bound ACs shown with the ATP-analogue R_P-ATPαS and the activator forskolin. In(a and b)C1 is coloured green and C2 red. (a) Activation by the G_sα (magenta) is thought to induce a 7° rotation of C1. The binding of the inhibitory G_iα (grey) is modelled on the opposite side of the structure on the basis of mapping studies. (b) The structure in (a) has been rotated to visualize the binding sites for G_βγ (blue loop) and calmodulin (Cam, grey helix) that have been mapped to C2 by mutational studies.(c)Overlay of structures without (beige) and with (red) bound ATP-analogue. The elements that show the largest displacements during closure of the catalytic site are coloured green (no substrate) and blue (with R_P-ATPαS).

AKAP, A kinase anchoring protein; RyR, ryanodine receptor, CICR, Ca²⁺ induced Ca²⁺ release; PKA, protein kinase A; PP1, protein phosphatase 1; PPase2B, protein phosphatase 2B ( alias calcineurin); PDE; cyclic nucleotide phosphodiesterase.

Persistent cAMP signalling by internalised receptors. cAMP responses triggered by activation of plasma membrane associated GPCRs are rapid, transient and result in a defined set of functional cellular outcomes. Signalling from Gαs coupled receptors can persist following receptor internalisation resulting in a more sustained cAMP response that can regulate a different set of cellular effects than those originating from the plasma membrane.

A, receptor agonist; AC, adenylyl cyclase.

Vilardaga JP, Romero G, Friedman PA, Gardella TJ. Molecular basis of parathyroid hormone receptor signaling and trafficking: a family B GPCR paradigm. Cell Mol Life Sci. 2011 Jan;68(1):1-13

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