Phosphodiesterases, 3′,5′-cyclic nucleotide (E.C.3.1.4.17)

Overview: 3′,5′-Cyclic nucleotide phosphodiesterases (PDEs, 3′,5′-cyclic-nucleotide 5′-nucleotidohydrolase) catalyse the hydrolysis of a 3′,5′-cyclic nucleotide (usually cyclic AMP or cyclic GMP). IBMX is a nonselective inhibitor with an IC₅₀ value in the millimolar range for all isoforms except PDE 8A, 8B and 9A. A 2′,3′-cyclic nucleotide 3′-phosphodiesterase (E.C. 3.1.4.37 CNPase) activity is associated with myelin formation in the development of the CNS.

Nomenclature	PDE1A	PDE1B	PDE1C	PDE2A
Other names	PDE I	PDE I	PDE I	PDE II, cGMP- stimulated cAMP-PDE, CGS-PDE
Ensembl ID	ENSG00000115252	ENSG00000123360	ENSG00000154678	SwissProt O00408
Rank order of affinity	cGMP > cAMP	cGMP > cAMP	cGMP = cAMP	cAMP >> cGMP
Activators	Ca2+/CaM	Ca2+/CaM	Ca2+/CaM	cGMP
Selective inhibitors	SCH51866 (7.2, Vemulapalli et al., 1996), vinpocetine (5.1, Loughney et al., 1996)	SCH51866 (7.2, Vemulapalli et al., 1996)	SCH51866 (7.2, Vemulapalli et al., 1996), vinpocetine (4.3, Loughney et al., 1996)	BAY607550 (8.3–8.8, Boess et al., 2004), EHNA (5.3, Michie et al., 1996)

PDE1A, 1B and 1C appear to act as soluble homodimers, while PDE2A is a membrane-bound homodimer. EHNA is also an inhibitor of adenosine deaminase (E.C. 3.5.4.4).

Nomenclature	PDE3A	PDE3B
Other names	PDE III, cGMP-inhibited cAMP-PDE, CGI-PDE A	PDE III, cGMP-inhibited cAMP-PDE, CGI-PDE B
Ensembl ID	ENSG00000172572	ENSG00000152270
Selective inhibitors	Cilostamide (7.5, Sudo et al., 2000), milrinone (6.3, Sudo et al., 2000), cGMP	Cilostamide (7.3, Sudo et al., 2000), milrinone (6.0, Sudo et al., 2000), cGMP

PDE3A and PDE3B are membrane-bound.

Nomenclature	PDE4A	PDE4B	PDE4C	PDE4D
Other names	PDE IV	PDE IV	PDE IV	PDE IV
Ensembl ID	ENSG00000065989	ENSG00000184588	ENSG00000105650	ENSG00000113448
Rank order of affinity	cAMP >> cGMP	cAMP >> cGMP	cAMP >> cGMP	cAMP >> cGMP
Activators	–	–	–	PKA-mediated phosphorylation (Houslay and Adams, 2003)
Selective inhibitors	Rolipram (9.0, Wang et al., 1997), YM976 (8.3, Aoki et al., 2000), Ro201724 (6.5, Wang et al., 1997)	Rolipram (9.0, Wang et al., 1997), Ro201724 (6.4, Wang et al., 1997)	Rolipram (6.5, Wang et al., 1997), Ro201724 (5.4, Wang et al., 1997)	Rolipram (7.2, Wang et al., 1997), Ro201724 (6.2, Wang et al., 1997)

PDE4 isoforms are essentially cAMP specific. The potency of YM976 at other members of the PDE4 family has not been reported. PDE4B–D long forms are inhibited by extracellular signal-regulated kinase (ERK)-mediated phosphorylation (Hoffmann et al., 1998; Hoffmann et al., 1999). PDE4A–D splice variants can be membrane-bound or cytosolic (Houslay and Adams, 2003). PDE4 isoforms may be labelled with [³H]-rolipram.

Nomenclature	PDE5A	PDE7A	PDE7B	PDE8A	PDE8B
Other names	PDE V, cGMP-specific PDE	HCP1	–	High-affinity cAMP- specific and IBMX- insensitive PDE	–
Ensembl ID	ENSG00000138735	ENSG00000104732	ENSG00000171408	ENSG00000073417	ENSG00000113231
Rank order of affinity	cGMP > cAMP	cAMP >> cGMP (Michaeli et al., 1993)	cAMP >> cGMP (Gardner et al., 2000)	cAMP >> cGMP (Fisher et al., 1998a)	cAMP >> cGMP (Hayashi et al., 1998)
Activators	PKA (Corbin et al., 2000), PKG (Corbin et al., 2000)	–	–	–	–
Selective inhibitors	T0156 (9.5, Mochida et al., 2002), sildenafil (9.0, Turko et al., 1999), SCH51866 (7.2, Vemulapalli et al., 1996), zaprinast (6.8, Turko et al., 1999)	BRL50481 (6.7, Smith et al., 2004)	Dipyridamole (5.7–6.0, Gardner et al., 2000); Sasaki et al., 2000), SCH51866 (5.8, Sasaki et al., 2000)	Dipyridamole (5.1, Fisher et al., 1998a)	Dipyridamole (4.3, Hayashi et al., 1998)

PDE7A appears to be membrane-bound or soluble for PDE7A1 and 7A2 splice variants, respectively. BRL50481 appears not to have been examined as an inhibitor of PDE7B.

Nomenclature	PDE9A	PDE10A	PDE11A
Ensembl ID	ENSG00000160191	ENSG00000112541	ENSG00000128655
Substrate specificity	cGMP >> cAMP (Fisher et al., 1998b)	cAMP, cGMP (Fujishige et al., 1999)	cAMP, cGMP (Fawcett et al., 2000)
Selective inhibitors	BAY736691 (7.3, Wunder et al., 2005)	Papaverine (7.4, Siuciak et al., 2006)	–

Nomenclature	PDE6A	PDE6B	PDE6C	PDE6D	PDE6G	PDE6H
Other names	cGMP-PDE α, PDE V-b1	cGMP-PDE β	cGMP-PDE α, PDEA2	cGMP-PDE δ	cGMP-PDE γ	cGMP-PDE γ
Ensembl ID	ENSG00000132915	ENSG00000133256	ENSG00000095464	ENSG00000156973	ENSG00000185527	ENSG00000139053

PDE6 is a membrane-bound tetramer composed of two catalytic chains (PDE6A or PDE6C and PDE6B), an inhibitory chain (PDE6G or PDE6H) and the PDE6D chain. The enzyme is essentially cGMP specific and is activated by the α-subunit of transducin (G_t) and inhibited by sildenafil, zaprinast and dipyridamole with potencies lower than those observed for PDE5A. Defects in PDE6B are a cause of retinitis pigmentosa and congenital stationary night blindness.

Glossary

Abbreviations:

BAY607550

2-(3,4-dimethoxybenzyl)-7-{(1R)-1-[(1R)-1-hydroxyethyl]-4-phenylbutyl}-5-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

1-BAY736691

(2-chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methylpropyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one

BRL50481

5-nitro-2,N,N-trimethylbenzenesulfonamide

EHNA

erythro-9-(2-hydroxy-3-nonyl)adenine

PKA

cyclic AMP-dependent protein kinase

PKG

cyclic GMP-dependent protein kinase

Ro201724

4-(3-butoxy-4-methoxyphenyl)methyl-2-imidazolidone

YM976

(4-[3-chlorophenyl]-1,7-diethylpyrido[2,3-d]pyrimidin-2(1H)-one)

SCH51866

cis-5,6a,7,8,9,9a-hexahydro-2-(4-[trifluoromethyl]phenylmethyl)-5-methyl-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one

Further Reading

Bjorgo E, Tasken K (2006). Role of cAMP phosphodiesterase 4 in regulation of T-cell function. Crit Rev Immunol26: 443–451.

Boswell-Smith V, Spina D, Page CP (2006). Phosphodiesterase inhibitors. Br J Pharmacol147(Suppl. 1) : S252–S257.

Currie GP, Butler CA, Anderson WJ, Skinner C (2008). Phosphodiesterase 4 inhibitors in chronic obstructive pulmonary disease: a new approach to oral treatment. Br J Clin Pharmacol65: 803–810.

Fan Chung K (2006). Phosphodiesterase inhibitors in airways disease. Eur J Pharmacol533: 110–117.

Halene TB, Siegel SJ (2007). PDE inhibitors in psychiatry–future options for dementia, depression and schizophrenia? Drug Discov Today12: 870–878.

Houslay MD, Baillie GS, Maurice DH (2007). cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. Circ Res100: 950–966.

Kass DA, Champion HC, Beavo JA (2007). Phosphodiesterase type 5: expanding roles in cardiovascular regulation. Circ Res101: 1084–1095.

Kodimuthali A, Jabaris SS, Pal M (2008). Recent advances on phosphodiesterase 4 inhibitors for the treatment of asthma and chronic obstructive pulmonary disease. J Med Chem51: 5471–5489.

Kumar P, Francis GS, Tang WH (2009). Phosphodiesterase 5 inhibition in heart failure: mechanisms and clinical implications. Nat Rev Cardiol6: 349–355.

McConnachie G, Langeberg LK, Scott JD (2006). AKAP signaling complexes: getting to the heart of the matter. Trends Mol Med12: 317–323.

Yamagata T, Ichinose M (2006). Agents against cytokine synthesis or receptors. Eur J Pharmacol533 : 289–301.