Phosphodiesterases

Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and/or cGMP. They function with adenylyl and guanylyl cyclases to regulate the amplitude and duration of responses triggered by the second messengers, cAMP and cGMP. In doing so they regulate a wide range of biological responses triggered by light, hormones, neurotransmitters and odorants. Two classes of functional PDEs, which do not share any sequence homology, are recognized: Class I PDEs, found in all eukaryotic cells and Class II PDEs, found in lower eukaryotes.

There are 11 different mammalian PDE families of which PDE4, PDE7 and PDE8 are specific for cAMP, while PDE5, PDE6 and PDE9 are specific for cGMP and others hydrolyze both cAMP and cGMP. PDE3, whose V_max cAMP > V_max cGMP and K_m cGMP < K_m cAMP, is generally considered as a cGMP-inhibited cAMP hydrolyzing PDE.

PDEs contain a conserved, catalytic domain of around 250 amino acids, where an invariant glutamine provides the key specificity determinant by scanning the purine moiety in cAMP/cGMP. Adjacent residues anchor this glutamine in different orientations so as to define specificity for either or both cAMP/cGMP.

Twenty-one genes encode the 11 known PDE families with additional isoform diversity generated through alternative mRNA splicing and the use of distinct promoters. Isoforms have an extreme N-terminal domain that uniquely characterizes them. In various PDE families, and particularly with PDE4, this is involved in intracellular targeting. Different cell types express a unique complement of PDE isoforms, thereby individually tailoring the nature of the spatial and kinetic characteristics of the cAMP signal. This defines the characteristics of compartmentalized cAMP signaling operating in such cells.

For various PDEs, located immediately N-terminal to the catalytic unit are family-specific paired regulatory domains. These allow regulation through cross-talk with various other signal transduction systems by either phosphorylation or allosteric regulation.

PDEs are named to identify isoforms. Thus, HSPDE4A1 refers to the Homo sapiens PDE4 family, gene A, splice variant 1. The high level of sequence conservation among species, distinct intracellular targeting and kinetic and regulatory characteristics suggest that individual PDEs play particular roles in specific physiological processes. For example, PDE1 isoforms have twin regulatory domains that allow them to bind and be activated by Ca²⁺/calmodulin, providing cross talk between the Ca²⁺ and cAMP/cGMP signaling pathways. They can participate in the feed-forward amplification of neuronal signals. PDE2 has twin regulatory GAF domains that allow binding and activation by cGMP, providing cross talk with the cGMP/NO signaling pathway. Indeed, PDE2A plays a role in regulating aldosterone production in adrenal glomerulosa cells through integration of cAMP and cGMP signals. PDE3, which hydrolyzes cAMP, has a unique insert in its catalytic region, which attenuates its cGMP hydrolyzising capacity such that cGMP potently inhibits cAMP hydrolysis by this enzyme. This allows elevation of cGMP to potentiate cAMP signals, which has functional significance in regulation of platelet aggregation. PDE3B underpins the anti-lipolytic action of insulin in adipocytes through being phosphorylated and activated by PKB/Akt. PDE3, together with PDE4 isoforms, provide the major cAMP hydrolyzing activity in many cells. PDE4 isoforms underpin much of compartmentalized cAMP signaling by interacting with a range of scaffold proteins, including barrestin, AKAPs, SRC kinases, myomegalin and RACK1. Their phosphorylation by ERK configures cross-talk with this pathway and phosphorylation by PKA promotes cAMP desensitization. Chemical and genetic knockout identifies PDE4s as having a key role in inflammatory responses, memory and depression. PDE5, has cGMP-binding, regulatory GAF domains and plays a role in regulating smooth muscle tension in certain vascular beds. Sildenafil, a selective PDE5A inhibitor, is used to treat erectile dysfunction. PDE6 plays a central role in visual phototransduction through rapid modulation of cGMP hydrolysis subsequent to activation by GTP-bound transducin. The functional significance of the newer PDEs is not well appreciated and they provide a challenge for the future in understanding their physiological roles.

The Table below contains accepted modulators and additional information. For a list of additional products, see the related products section below.

Family Name	PDE1	PDE2	PDE3	PDE4	PDE5
Known Genesa	1A, 1B, 1C	2A	3A, 3B	4A, 4B, 4C, 4D	5A
Descriptive Name	CaM-dependent PDE	cGMP-stimulated PDE	cGMP-inhibited PDE	cAMP-specific PDE	cGMP-binding PDE
Structural Informationb	535 aa (human) HSPDE1A3	941 aa (human) HSPDE2A3	1141 aa (human) HSPDE3A1	647 aa (human) HSPDE4A1	874 aa (human) HSPDE5A1
Regulators	Ca2+/CaM (21272)	cGMP (G6129)	cGMP (G6129) Insulin (I5500 (b), I2643 (h)) Leptin (L4146 (h), L3772 (m), L5037 (r))	PKA (P5511) ERK Phosphatidic acid (P9511)	PKG
Substrate Specificity	cAMP (A6885) or cGMP (G6129)	cAMP (A6885) or cGMP (G6129)	cAMP (A6885) or cGMP (G6129)	cAMP (A6885)	cGMP (G6129)
Inhibitorsc	Vinpocetine (V6383)d SCH-51866d	*EHNA (E114) *BAY60-7550	*Cilostamide (C7971) Enoximone (E1279) Imazodan (I0782) Trequinsin (T2057) Milrinone (M4659)	*Rolipram (R6520) *Ro20-1724 (B8279) *RP 73401 (SML0585)	*Sildenafil (PZ0003) *Vardenafil Dipyridamole (D9766)d T-1032 Zaprinast (Z0878)d
Major Tissue Expression	Brain, heart, smooth muscle, olfactory cilia	Adrenal cortex Brain Heart	Heart Adipose Pancreas Platelets	Many tissues	Lung Platelets Smooth muscle Corpus collusum
Physiological Function	Sperm development and maturation Monocyte/macrophage differentiation Olfactory neuron regulation Neuronal regulation	β2/β3 regulation of cardiac myocytes Endothelial cell function	Platelet function Adipocyte function	Regulates monocyte, macrophage T-cell, eosinophil, neutrophil function Regulates neuronal function and differentiation Regulates functions of inflammatory cells and vascular smooth muscle cells Pro-apoptotic Anti-apoptotic Endothelial cell function Inhibition of bone loss	Vascular smooth muscle cell relaxation
Disease Relevance	Fertility Inflammation Olfaction	Heart disease Anti-angiogenic	Intermittent claudication peripheral arterial occlusive disease Restenosis Obesity Type-2 diabetes	Airway inflammation (asthma, COPD) Rheumatoid arthritis Crohn's disease Learning Memory Schizophrenia Spinal cord injury Stroke Restenosis Chronic B-cell lymphocytic leukemia Spinal cord injury Parkinson's Disease Anti-angiogenic Osteopenia (including osteoporosis)	Penile erectile dysfunction Asthma COPD Pulmonary hypertension Migraine

Family Name	PDE6	PDE7	PDE8	PDE9	PDE10	PDE11
Known Genesa	6A, 6B	7A, 7B	8A, 8B	9A	10A	11A
Descriptive Name	Photoreceptor PDE	High affinity cAMP-specific PDE	cAMP-specific PDE	High affinity cGMP-specific PDE	Dual specificity PDE	Dual specificity PDE
Structural Informationb	860 aa (human) HSPDE6A1	482 aa (human) HSPDE7A1	713 aa (human) HSPDE8A1	593 aa (human) HSPDE9A1	779 aa (human) HSDPE10A1	490 aa (human) HSPDE11A1
Regulators	Light	Not Known	Not Known	Not Known	PKA (P5511)	Not Known
Substrate Specificity	cGMP (G6129)	cAMP (A6885)	cAMP (A6885)	cGMP (G6129)	cAMP (A6885) or cGMP (G6129)	cAMP (A6885) or cGMP (G6129)
Inhibitorsc	Zaprinast (Z0878)d Dipyridamole (D9766)d	BRL50481 (B0936)	Dipyridamole (D9766)d	SCH-51866d	SCH-51866d Zaprinast (Z0878)d Dipyridamole (D9766)d	Zaprinast (Z0878)d Dipyridamole (D9766)d
Major Tissue Expression	Rod and cone Photoreceptor Outer segments	Skeletal muscle T-cells	Testis Liver Thyroid	Kidney	Testis Brain	Skeletal muscle Prostate
Physiological Function	Visual signal transduction	Not Known	Thyroid function T-cell activation	Not Known	Striatal neuron function	Sperm function (motility, number)
Disease Relevance	Retinitis pigmentosa		Hyperthyroidism Metabolic bone disease	Fertility	Parkinsonism Schizophrenia Obsessive compulsive disorders Addictions	Fertility

Footnotes

a) Multiple splice variants exist for most of these enzymes. See reviews for a more complete listing and nomenclature.

b) One particular splice variant is listed from each PDE family. HS = Homo sapiens.

c) Several compounds act as non-selective inhibitors of most cyclic nucleotide phosphodiesterases including 3-isobutyl-1-methylxanthine (IBMX I5879), theophylline (T1633), papaverine (P3510), pentoxyfylline (P1784) and 1,3-dipropyl-7-methylxanthine (D108).

d) Selective inhibitors for the PDE1, PDE6, PDE7, PDE8, PDE9, PDE10 and PDE11 families are not currently available. Similarly, the compounds zaprinast and dipyridamole, once thought to be reasonably selective for the PDE5 and PDE6 families, are now known to also inhibit the PDE8, PDE10 and PDE11 families.

*Specific inhibitors that achieve reversible chemical inhibition of this particular family only.

Abbreviations

CaM: Calmodulin
EHNA: Erythro-9-(2-hydroxy-3-nonyl)adenine
PKA: cAMP-dependent protein kinase
PKG: cGMP-dependent protein kinase
Ro 20-1724: 4-[(3-Butoxy-4-methoxyphenyl)methyl]2-imidazolidinone
RP 73401: N-(3,5-Dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide
SB-207499: c-4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl-r-1-cyclohexane carboxylic acid)
SCH-51866: cis-5,6a,7,8,9,9a-Hehahydro-2-[4-(trifluoromethyl)phenylmethyl]-5-methyl-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one
T-1032: Methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate

b: bovine
h: human
m: mouse
r: rat

References

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