cAMP and cGMP signalling

Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are second messengers for intracellular signal transduction. cAMP and cGMP signalling complex, involving numerous enzymes, receptors and effectors, and is compartmentalized within cells.

cAMP

G protein-coupled receptors (GPCRs) that are coupled with GαS can stimulate adenylyl cyclase (AC) activity, and thus increase cAMP production from ATP. Several isoforms of AC exist, with different localization and GPCR coupling preferences. cGMP signalling is terminated by cGMP hydrolysis via PDEs, especially PDE4D.

cGMP

cGMP is produced from GTP by soluble guanylyl cyclase (sGC) and particulate guanylyl cyclase (pGC). The former is activated by nitric oxide (NO), and the latter by natriuretic peptides (NPs). cGMP signalling is terminated by cGMP hydrolysis via PDEs and cGMP export via ABC transporters.

PDEs

Cyclic nucleotide phosphodiesterases (PDEs) break the phosphodiester bond in cAMP and cGMP, thus ending subcellular signalling by these second messenger molecules. PDEs have different substrate specificities: PDE4, PDE7 and PDE8 are cAMP-selective hydrolases; PDE5, PDE6 and PDE9 are cGMP-selective; and PDE1, PDE2, PDE3, PDE10 and PDE11 can hydrolyse both cAMP and cGMP.

[18F]PF-05270430 is selective radioligand for PDE2A, and suitable for brain PET imaging, although BPND is relatively low (Naganawa et al., 2016; Chen et al., 2016).

(R)-[11C]rolipram can be used to assess PDE4 activity in the heart and brain of rats (Lourenco et al., 2006; Thomas et al., 2011).

[11C]MTP38 is a reversible radioligand for imaging PDE7A in human brain (Kubota et al., 2021; Obokata et al., 2021).

Several PET radioligands targeting PDE10A have been developed, including [11C]IMA107 (Plisson et al., 2014), [11C]Lu AE92686 (Kehler et al., 2014; Yang et al., 2017), [11C]T-773 (Takano et al., 2016), and [18F]JNJ-42259152 (Van Laere et al., 2013).


See also:



Literature

Friebe A, Sandner P, Schmidtko A. cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development. Naunyn Schmiedebergs Arch Pharmacol. 2020; 393(2): 287–302. doi: 10.1007/s00210-019-01779-z.

Johnstone TB, Agarwal SR, Harvey RD, Ostrom RS. cAMP signaling compartmentation: adenylyl cyclases as anchors of dynamic signaling complexes. Mol Pharmacol. 2018; 93(4): 270-276. doi: 10.1124/mol.117.110825.

Schlossmann J, Schinner E. cGMP becomes a drug target. Naunyn Schmiedebergs Arch Pharmacol. 2012; 385(3): 243-252. doi: 10.1007/s00210-012-0730-6.

Schröder S, Scheunemann M, Wenzel B, Brust P. Challenges on cyclic nucleotide phosphodiesterases imaging with positron emission tomography: novel radioligands and (pre-)clinical insights since 2016. Int J Mol Sci. 2021; 22(8): 3832. doi: 10.3390/ijms22083832.

Zaccolo M, Zerio A, Lobo MJ. Subcellular organization of the cAMP signalling pathway. Pharmacol Rev. 2021; 73(1): 278-309. doi: 10.1124/pharmrev.120.000086.



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Updated at: 2021-12-23
Created at: 2021-12-07
Written by: Vesa Oikonen