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.
PDE2A is highly expressed in limbic structures and basal ganglia of the brain, especially in glutamate synapses (Chen et al., 2016). PDE2A is linked to synaptic plasticity and cognitive function. PDE2A inhibitors could be used in treatment of migraine, neurodegenerative diseases, and schizophrenia. [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). PDE4B-specific [18F]PF-06445974 is suitable, although not optimal, for imaging human brain (Wakabayashi et al., 2022).
PDE5 is present in practically all human cell types and organs, and cancer cells may overexpress PDE5 (Peng et al., 2018). PDE5 inhibitors sildenafil and tadalafil can be used to treat pulmonary arterial hypertension and erectile dysfunction. Sildenafil increases uncoupling protein 1 (UCP1) expression and induces browning of WAT. PDE5 inhibitors may be useful in treatment of neuroinflammation and neurodegeneration. Several PDE5 inhibitors have been labelled with 11C and 18F, but PET imaging results have so far been disappointing (Bailey et al., 2021).
PDE7 subtypes are present in the mammalian heart, liver, skeletal muscles, kidneys, ovaries, testes, and pancreas, but the distribution patterns vary among different species. PDE7 is implicated in pro-inflammatory processes, and PDE7 inhibitors may be useful in treatment of inflammatory disorders and some cancer types. [11C]MTP38 is a reversible radioligand for imaging PDE7A in human brain (Kubota et al., 2021; Obokata et al., 2021).
In brain, PDE10A is expressed primarily in the striatum and basal ganglia. 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 ([11C]KIT-6) (Takano et al., 2016), [18F]JNJ-42259152 (Van Laere et al., 2013), [11C]TZ1964B Liu et al., 2015, and [18F]MNI-659 (Kubota et al., 2022). These have been applied in PET studies of schizophrenia, PD, and HD
See also:
Literature
Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev. 2011; 91(2): 651-690. doi: 10.1152/physrev.00030.2010.
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.
Sun J, Xiao Z, Haider A, Gebhard C, Xu H, Luo HB, Zhang HT, Josephson L, Wang L, Liang SH. Advances in cyclic nucleotide phosphodiesterase-targeted PET imaging and drug discovery. J Med Chem. 2021; 64(11): 7083-7109. doi: 10.1021/acs.jmedchem.1c00115.
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.
Updated at: 2023-01-26
Created at: 2021-12-07
Written by: Vesa Oikonen