Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erection is basically a spinal reflex that can be initiated by recruitment of penile afferents, but also by visual, olfactory, and imaginary stimuli. The reflex involves both autonomic and somatic efferents and is modulated by supraspinal influences. Several central transmitters involved in the erectile control have been identified. Dopamine, acetylcholine, nitric oxide (NO), and peptides, such as oxytocin and adrenocorticotropic/alpha-melanocyte-stimulating hormone, seem to have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. Peripherally, the balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa and determines the functional state of the penis. Noradrenaline contracts both corpus cavernosum and penile vessels via stimulation of alpha(1)-adrenoceptors. Neurogenic NO is considered the most important factor for relaxation of penile vessels and corpus cavernosum. The role of other mediators released from nerves or endothelium has not been definitely established. Erectile dysfunction (ED) may be due to inability of penile smooth muscles to relax. This inability can have multiple causes. However, patients with ED respond well to the pharmacological treatments that are currently available. The drugs used are able to substitute, partially or completely, the malfunctioning endogenous mechanisms that control penile erection. Most drugs have a direct action on penile tissue facilitating penile smooth muscle relaxation, including prostaglandin E(1), NO donors, phosphodiesterase inhibitors, and alpha-adrenoceptor antagonists. Dopamine receptors in central nervous centers participating in the initiation of erection have been targeted for the treatment of ED. Apomorphine, administered sublingually, is the first of such drugs.
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PMID:Pharmacology of penile erection. 1154 36

We studied the actions of D1 and D2 dopamine agonists and antagonists on the coupling of horizontal cell axons in the turtle retina by a combination of pharmacological and electrophysiological methods. Both D1 and D2 receptors were identified in membrane fractions by radioligand binding using [3H]-SCH 23390 and [3H]-spiperone, respectively. The KD of both receptor classes were identical (0.21 nM) but D1 receptor density exceeded that of D2 receptors by more than four-fold. D1 agonists increased the activity of adenylate cyclase in a dose-dependent manner, whereas D2 agonists were without significant effect by themselves, nor did D2 antagonists block the D1-mediated increase in adenylate cyclase activity. Intracellular recordings and Lucifer Yellow dye injections were used to characterize the modifications of the receptive field profile of horizontal cell axons (H1AT) exposed to different pharmacological agents. Dopamine or D1 agonists (0.05 - 10 microM) induced a marked constriction of the H1AT receptive field, whereas D2 agonists elicited a small expansion of the receptive field. However, in the presence of a D1 antagonist, as well as IBMX to inhibit phosphodiesterase, D2 agonists (10 - 70 microM) induced a marked increase in the receptive field profile. These results indicate that both D1 and D2 dopamine receptors play a role in shaping the receptive field profile of the horizontal cell axon terminal in the turtle retina.
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PMID:Involvement of D1 and D2 Dopamine Receptors in the Control of Horizontal Cell Electrical Coupling in the Turtle Retina. 1210 55

Dopamine, by activating dopamine D1-type receptors, and adenosine, by activating adenosine A(2A) receptors, stimulate phosphorylation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of M(r) 32,000) at Thr-34. In this study, we investigated the effect of metabotropic glutamate (mGlu) receptors on DARPP-32 phosphorylation at Thr-34 in neostriatal slices. A broad-spectrum mGlu receptor agonist, trans-ACPD, and a group I mGlu receptor agonist, DHPG, stimulated DARPP-32 phosphorylation at Thr-34. Studies with mGlu receptor antagonists revealed that the effects of trans-ACPD and DHPG were mediated through activation of mGlu5 receptors. The action of mGlu5 receptors required activation of adenosine A(2A) receptors by endogenous adenosine. Conversely, the action of adenosine A(2A) receptors required activation of mGlu5 receptors by endogenous glutamate. Coactivation of mGlu5 and adenosine A(2A) receptors by exogenous agonists synergistically increased DARPP-32 phosphorylation. mGlu5 receptors did not require activation of dopamine D1-type receptors by endogenous dopamine, nor did dopamine D1-type receptors require activation of mGlu5 receptors by endogenous glutamate. DHPG potentiated the effect of forskolin, but not that of 8-bromo-cAMP, and stimulated DARPP-32 phosphorylation in the presence of the phosphodiesterase inhibitor IBMX, suggesting that mGlu5 receptors stimulate the rate of cAMP formation coupled to adenosine A(2A) receptors. The action of mGlu5 receptors was attenuated by inhibitors of extracellular signal-regulated kinase, but not by inhibitors of phospholipase C, p38, casein kinase 1, or Cdk5. The results demonstrate that mGlu5 receptors potentiate adenosine A(2A)DARPP-32 signaling by stimulating the adenosine A(2A) receptor-mediated formation of cAMP in an extracellular signal-regulated kinase-dependent manner.
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PMID:Metabotropic mGlu5 receptors regulate adenosine A2A receptor signaling. 1253 71

Dopamine and NO are physiological stimulators of synthesis of cAMP and cGMP, respectively, and NO synthase-containing interneurons in the striatum are physiologically activated by dopamine-containing neurons in the substantia nigra. This study investigated whether lesioning dopamine neurons has multiple consequences in the striatum consistent with the reported sensitization of cAMP synthesis, including alteration of the NO-cGMP pathway and phosphodiesterase-dependent metabolism of cyclic nucleotides. The substantia nigra of adult Sprague-Dawley rats was unilaterally lesioned with 6-hydroxydopamine. Two months later, we determined expression of NO synthase and evaluated cGMP and cAMP levels of intact and deafferented striatum. Moreover, we evaluated cAMP- and cGMP-phosphodiesterase activities in basal conditions and after Ca2+-calmodulin stimulation and determined the expression of the phosphodiesterase-1B isoform and the levels of phosphodiesterase-1B mRNA. Using immunocytochemistry we characterized the distribution of NO synthase and phosphodiesterase-1B within striatal neurons. In the dopamine-deafferented striatum, NO synthase levels were decreased by 42% while NO synthase-immunopositive intrastriatal fibres but not NO synthase neuronal bodies were reduced in number. In the deafferented striatum basal cGMP levels were reduced, and cAMP levels were increased, but cGMP-phosphodiesterase and cAMP-phosphodiesterase activities were both increased in basal and Ca2+-calmodulin-stimulated conditions. Accordingly, phosphodiesterase-1B expression and phosphodiesterase-1B mRNA were upregulated while a large population of medium-sized striatal neurons showed increased phosphodiesterase-1B immunoreactivity. Dopamine deafferentation led to a complex down-regulation of the NO-cGMP pathway in the striatum and to an up-regulation of phosphodiesterase-1B-dependent cyclic nucleotide metabolism, showing new aspects of neuronal plasticity in experimental hemiparkinsonism.
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PMID:Down-regulation of nitrergic transmission in the rat striatum after chronic nigrostriatal deafferentation. 1530 67

Diazepam inhibits phosphodiesterase type 4 and enhances the effect of some 3',5'-cyclic adenosine monophosphate (cAMP)-dependent positive inotropic drugs. We sought to determine whether diazepam and the selective phosphodiesterase type 4 inhibitor rolipram enhances the contractile response and cAMP levels induced by dopamine in rat myocardium. Dopamine (3-100 microM) produced concentration-dependent positive inotropic effects (-log EC50 = 5.21 +/- 0.2, n = 5), which were augmented in the presence of 10 microM diazepam (-log EC50 = 5.40 +/- 0.08, n = 6, P < 0.05) or 1 microM rolipram (-log EC50 = 5.41 +/- 0.1, n = 6, P < 0.05). The effect of diazepam was not mimicked by 100 microM gamma-aminobutyric acid nor it was antagonized by a 5 microM concentration of the blockers of central and peripheral type benzodiazepine receptors, flumazenil and PK 11195. cAMP levels (pmol/g) produced by dopamine (744.4 +/- 111.8, n = 5) in this tissue were enhanced by the presence of diazepam (1073 +/- 97.7, n = 6, P < 0.05) or rolipram (1034.0 +/- 245.2, n = 5, P < 0.05). Therefore, diazepam, like rolipram, augments the inotropic and biochemical effects of dopamine in rat myocardium. This effect is not mediated by benzodiazepine receptors but is probably the consequence of the phosphodiesterase type 4 inhibitory activity of diazepam.
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PMID:Diazepam enhances inotropic responses to dopamine in rat ventricular myocardium. 1649 14

Dopamine D1 receptors (D1) in the prefrontal cortex have been implicated in the modulation of cognitive processes as well as both positive and negative symptoms of schizophrenia. Therefore pharmacologic agents with potent D1 effects such as clozapine may influence the symptoms of schizophrenia (SCZ). Genetic variation in the D1 receptor gene (DRD1) may help to explain some of the variability in patient response to antipsychotics (APs). This study investigates the effect of four single nucleotide polymorphisms (SNPs) in DRD1 on clozapine response in two distinct SCZ populations (Caucasian and African American) refractory or intolerant to conventional APs. This study included 183 Caucasian and 49 African American schizophrenics diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (revised third or fourth edition). Genotyping was determined by 5'-exonuclease fluorescence assays. Within each population genotype, allele, allele +/- and haplotype frequencies were compared against dichotomous and quantitative measures of treatment response. Linkage disequilibrium analysis was also performed. In the Caucasian sample, no associations were observed for individual SNP tests. However, a rare three-marker haplotype predicted poor response. In the African American sample, the rs265976 variant and another three-marker haplotype were associated with cLozapine response. Although we did not find an association between the rs4532 SNP (-48 A/G, recognized by a DdeI restriction cut site) and cLozapine response as reported by Potkin et al. (2003), a trend in the same direction was observed as well. Our findings suggest that the rs4532 SNP may have a small effect if any. Further studies in larger, independent samples are required to validate these findings.
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PMID:Association study of four dopamine D1 receptor gene polymorphisms and clozapine treatment response. 1709 69

Autosomal-dominant striatal degeneration (ADSD) is an autosomal-dominant movement disorder affecting the striatal part of the basal ganglia. ADSD is characterized by bradykinesia, dysarthria, and muscle rigidity. These symptoms resemble idiopathic Parkinson disease, but tremor is not present. Using genetic linkage analysis, we have mapped the causative genetic defect to a 3.25 megabase candidate region on chromosome 5q13.3-q14.1. A maximum LOD score of 4.1 (Theta = 0) was obtained at marker D5S1962. Here we show that ADSD is caused by a complex frameshift mutation (c.94G>C+c.95delT) in the phosphodiesterase 8B (PDE8B) gene, which results in a loss of enzymatic phosphodiesterase activity. We found that PDE8B is highly expressed in the brain, especially in the putamen, which is affected by ADSD. PDE8B degrades cyclic AMP, a second messenger implied in dopamine signaling. Dopamine is one of the main neurotransmitters involved in movement control and is deficient in Parkinson disease. We believe that the functional analysis of PDE8B will help to further elucidate the pathomechanism of ADSD as well as contribute to a better understanding of movement disorders.
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PMID:Autosomal-dominant striatal degeneration is caused by a mutation in the phosphodiesterase 8B gene. 2008 14

Dopamine (DA; 1-100 ?M) alone did not significantly stimulate cyclic AMP accumulation in the hen retina; however, in the presence of 0.3 ?M spiroperidol, it clearly increased it. DA, in a concentration-dependent manner, enhanced the stimulatory effect of forskolin (1 and 10 ?M), both in the absence and presence of a phosphodiesterase (PDE) inhibitor IBMX (0.5 mM). A selective D1-receptor blocker such as SCH 23390 antagonized the activating effect of DA when used at 1 ?M, and reversed the amine action from a stimulatory into an inhibitory effect when applied at 3 or 10 ?M concentration. Addition of 0.3 ?M spiroperidol further enhanced the DA action on cyclic AMP accumulation evoked by forskolin; however, spiroperidol used at 5 ?M concentration antagonized the potentiating effect of the amine. Selective agonists of DA D2-receptors such as quinpirole (LY 1715550; 0.01-10 ?M) and bromocriptine (1-100 ?M) decreased both basal levels and forskolin-stimulated cyclic AMP accumulation in a concentration-dependent manner in the absence and presence of 0.5 mM IBMX. Under daylight conditions, dibutyryl-cyclic AMP (1 mM) and a combination of 50?M forskolin and 0.1 mM IBMX (these drugs applied separately were only weakly active) significantly enhanced the activity of serotonin N-acetyltransferase (NAT) activity (the key regulatory enzyme in melatonin biosynthesis) in pieces of the hen retina. Quinpirole (0.001-10 ?M) inhibited the effect of forskolin (combined with IBMX) in a concentration-dependent and spiroperidol-sensitive manner, and did not modify the action of dibutyrylcyclic AMP. It is concluded that the hen retina possesses both types of DA receptors, i.e. D1 and D2, whose stimulation respectively increase and decrease cyclic AMP levels. These D2-receptors, which are negatively coupled to adenylate cyclase, seem to be involved in the regulation of NAT activity in the retina, and their activation leads to the inhibition of the enzyme induction.
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PMID:Activation of D2 dopamine receptors in hen retina decreases forskolin-stimulated cyclic AMP accumulation and serotonin N-acetyltransferase (NAT) activity. 2050 42

Cellular depolarization in brain results in a modulation of cAMP levels by releasing neurotransmitters having receptors linked via GTP-binding proteins to adenylate cyclase. In order to determine the transmitters regulating cAMP during cellular depolarization in mammalian retina, the modulation of cAMP by depolarizing media was investigated. Cyclic AMP levels in light adapted retinas increased following exposure to depolarizing media, but levels in dark adapted retinas remained unaltered. The depolarization-induced modulation of cAMP levels persisted in dystrophic retinas, suggesting that the response occurred in the inner retina. In microdissected discrete retinal layers from rabbit, levels of cAMP were increased following perfusion with depolarizing medium in the outer plexiform and inner nuclear layers, consistent with the observation seen with mouse retinas. To begin to identify transmitters released by cellular depolarization, a variety of transmitters and/or antagonists were included in the incubation medium. Haloperidol reduced the depolarization induced increase in cAMP levels by 25% in normal mouse retinas, and 75% in dystrophic retinas. Dopamine elevated cAMP levels in normal and dystrophic mouse retinas, and when combined with depolarizing medium, additive increases were observed. The effects of various neurotransmitters on retinal cAMP levels in the absence of any phosphodiesterase inhibitors were assessed, and both dopamine and norepinephrine were found to increase cAMP levels in normal and dystrophic retinas. Phentolamine antagonized the increase elicited by norepinephrine. When dopamine and norepinephrine were combined non-additive increases were observed. Serotonin, GABA, acetylcholine, histamine and adenosine had little or no significant effect on the retinal levels of cAMP in either normal or dystrophic mouse retinas. These results indicate that depolarizing media increase cAMP levels partially by releasing dopamine. The processes regulating cAMP levels in retina are both different and similar to those in brain.
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PMID:Regulation of cyclic AMP levels in mammalian retina: Effects of depolarizing agents and transmitters. 2050 42

Dopamine plays a central role in the regulation of psychomotor functions. The effect of dopamine is largely mediated through the cAMP/PKA signaling cascade and therefore controlled by phosphodiesterases (PDEs). Multiple PDEs with different substrate specificities and subcellular localization are expressed in the striatum, and the functional roles of PDE10A, PDE4, and PDE1B are extensively studied. Biochemical and behavioral profiles of PDE inhibition by selective inhibitors and/or genetic deletion related to dopaminergic neurotransmission are compared among those PDEs. The inhibition of PDE up-regulates cAMP/PKA signaling in three neuronal subtypes, resulting in the stimulation of dopamine synthesis at dopaminergic terminals, the inhibition of dopamine D(2)-receptor signaling in striatopallidal neurons, and the stimulation of dopamine D(1)-receptor signaling in striatonigral neurons. Predominant roles of PDE families or isoforms are implicated in each neuronal subtype: PDE4 at dopaminergic terminals, PDE10A and PDE4 in striatopallidal neurons, and PDE1B in striatonigral neurons. PDE10A and PDE4 inhibition may exhibit D(2) antagonist-like, antipsychotic effects, whereas PDE1B inhibition may exhibit D(1) agonist-like effects in the striatum. Development of PDE isoform-specific inhibitors is essential for better understanding of the function of each PDE isoform and treatment of neuropsychiatric disorders.
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PMID:Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: biochemical and behavioral profiles of phosphodiesterase inhibition in dopaminergic neurotransmission. 2071 58


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