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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 Vmax cAMP > Vmax cGMP and Km cGMP < Km 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 "Similar 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

 

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References