Clinical Catecholamine Neurochemistry: A Legacy of Julius Axelrod

Goldstein, David S.; Eisenhofer, Graeme; Kopin, Irwin J.

doi:10.1007/s10571-006-9041-0

Cited by 13 publications

(13 citation statements)

References 27 publications

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“…Instead we found, through investigating the orphan GPCR GPR88, which is targeted to cilia in our model system to a similar degree as the D1R, a discrete effect of primary cilia on the selectivity of GPR88-dependent regulation of the D1R relative to B2AR -mediated signaling response. Because the D1R and B2AR mediate cellular responses to distinct endogenous catecholamines and produce differential effects on target tissues [24], this suggests that primary cilia play a fundamental role in enhancing the selectivity of integrated catecholamine signaling.…”

Section: Discussionmentioning

confidence: 99%

GPR88 Reveals a Discrete Function of Primary Cilia as Selective Insulators of GPCR Cross-Talk

2013

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A number of G protein-coupled receptors (GPCRs) localize to primary cilia but the functional significance of cilia to GPCR signaling remains incompletely understood. We investigated this question by focusing on the D1 dopamine receptor (D1R) and beta-2 adrenergic receptor (B2AR), closely related catecholamine receptors that signal by stimulating production of the diffusible second messenger cyclic AMP (cAMP) but differ in localization relative to cilia. D1Rs robustly concentrate on cilia of IMCD3 cells, as shown previously in other ciliated cell types, but disrupting cilia did not affect D1R surface expression or ability to mediate a concentration-dependent cAMP response. By developing a FRET-based biosensor suitable for resolving intra- from extra- ciliary cAMP changes, we found that the D1R-mediated cAMP response is not restricted to cilia and extends into the extra-ciliary cytoplasm. Conversely the B2AR, which we show here is effectively excluded from cilia, also generated a cAMP response in both ciliary and extra-ciliary compartments. We identified a distinct signaling effect of primary cilia through investigating GPR88, an orphan GPCR that is co-expressed with the D1R in brain, and which we show here is targeted to cilia similarly to the D1R. In ciliated cells, mutational activation of GPR88 strongly reduced the D1R-mediated cAMP response but did not affect the B2AR-mediated response. In marked contrast, in non-ciliated cells, GPR88 was distributed throughout the plasma membrane and inhibited the B2AR response. These results identify a discrete ‘insulating’ function of primary cilia in conferring selectivity on integrated catecholamine signaling through lateral segregation of receptors, and suggest a cellular activity of GPR88 that might underlie its effects on dopamine-dependent behaviors.

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Section: Discussionmentioning

confidence: 99%

GPR88 Reveals a Discrete Function of Primary Cilia as Selective Insulators of GPCR Cross-Talk

2013

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“…The amino acid tyrosine (Tyr) gives origin to catecholamines [17], whereas tryptophan (Trp) is a substrate for 5-HT biosynthesis [18]. …”

Section: Synthesis and Metabolism Of Biogenic Amines In Parkinson’s Dmentioning

confidence: 99%

“…However, almost half a century ago, Ulf von Euler, Julius Axelrod, and Sir Bernard Katz described humoral transmitters in the nerve terminals and the mechanism for their storage, release, and catecholamine inactivation [17]. DA is synthetized by dopaminergic neurons, mostly located in the SN and other areas of the brain comprising the dopaminergic system [1, 2, 20].…”

Section: Synthesis and Metabolism Of Biogenic Amines In Parkinson’s Dmentioning

confidence: 99%

“…The second step of catecholamine biosynthesis is decarboxylation of L-dopa to DA. This reaction requires the presence of pyridoxal phosphate (active form of vitamin B6), and is catalyzed by the enzyme AADC (also described as L-dopa decarboxylase or 5-HTP decarboxylase) [4, 17]. DA is a substrate for the next reaction – β-hydroxylation (performed by an enzyme dopamine β-hydroxylase, DBH) – yielding NE.…”

Section: Synthesis and Metabolism Of Biogenic Amines In Parkinson’s Dmentioning

confidence: 99%

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Polymorphism of the COMT, MAO, DAT, NET and 5-HTT Genes, and Biogenic Amines in Parkinson’s Disease

Dorszewska¹,

Prendecki²,

Oczkowska³

et al. 2014

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Epinephrine (E) and sympathetic nerve stimulation were described by Thomas Renton Elliott in 1905 for the first time. Dopamine (DA), norepinephrine (NE), E, and serotonin (5-HT) belong to the classic biogenic amines (or monoamines). Parkinson’s disease (PD) is among the diseases in which it has been established that catecholamines may account for the neurodegeneration of central and peripheral catecholamine neural systems. PD is a chronic and progressive neurological disorder characterized by resting tremor, rigidity, and bradykinesia, affecting 2% of individuals above the age of 65 years. This disorder is a result of degeneration of DA-producing neurons of the substantia nigra and a significant loss of noradrenergic neurons in the locus coeruleus. In PD and other related neurodegerative diseases, catecholamines play the role of endogenous neurotoxins. Catechol-O-methyltransferase (COMT) and/or monoamine oxidase (MAO) catalyze the metabolism of monoamines. However, the monoamine transporters for DA, NE, and 5-HT namely DAT, NET, and SERT, respectively regulate the monoamine concentration. The metabolism of catecholamines and 5-HT involves common factors. Monoamine transporters represent targets for many pharmacological agents that affect brain function, including psychostimulators and antidepressants. In PD, polymorphisms of the COMT, MAO, DAT, NET, and 5- HTT genes may change the levels of biogenic amines and their metabolic products. The currently available therapies for PD improve the symptoms but do not halt the progression of the disease. The most effective treatment for PD patients is therapy with L-dopa. Combined therapy for PD involves a DA agonist and decarboxylase, MAOs and COMT inhibitors, and is the current optimal form of PD treatment maintaining monoamine balance.

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“…The biosynthetic activity of PNMT , the terminal enzyme of the catecholaminergic pathway, converts epinephrine from norepinephrine by N-methylation, thereby replenishing depleted stores [4,6]. Genetic single nucleotide polymorphism (SNP) analyses have commonly been employed in the study of complex disease traits.…”

Section: Introductionmentioning

confidence: 99%

Phenylethanolamine N-Methyltransferase Gene Polymorphisms and Adverse Outcomes in Acute Kidney Injury

Alam

O’Connor²,

Perianayagam³

et al. 2010

Nephron Clin Pract

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Background/Aims: The catecholaminergic pathway is important in the physical stress response; however, its role is not well understood in acute kidney injury (AKI). We studied single nucleotide polymorphisms (SNPs) of phenylethanolamine N-methyltransferase (PNMT), the terminal enzyme of the catecholaminergic pathway, and their association with adverse outcomes in AKI. Methods: We performed a case-control study of 961 Caucasian subjects (194 with AKI and 767 controls). The PNMT promoter G–161A (rs876493) and coding A+1543G (rs5638) SNPs were genotyped and haplotypes generated. The outcomes of interest were the development of AKI, in-hospital mortality, dialysis requirement, oliguria, and hemodynamic shock. Urine catecholamines were measured in cases to explore genotype-phenotype correlations. Results: The PNMT +1543 G allele was associated with AKI [odds ratio (OR) 2.19, 95% confidence interval (CI): 1.04–4.60]. For AKI cases, each PNMT –161 A allele was associated with lower mortality (OR 0.58, 95% CI: 0.35–0.99) and hemodynamic shock (OR 0.63, 95% CI: 0.40–1.00). The PNMT +1543 G allele was associated with oliguria (OR 3.35, 95% CI: 1.13–9.95). Urine adrenaline was associated with increased hemodynamic shock and mortality, but was lowest in PNMT –161 A/A carriers. Conclusion: In Caucasians, PNMT SNPs are associated with the development of AKI, disease severity, and in-hospital mortality. The adrenergic pathway provides another area of focus in the study of AKI.

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Clinical Catecholamine Neurochemistry: A Legacy of Julius Axelrod

Cited by 13 publications

References 27 publications

GPR88 Reveals a Discrete Function of Primary Cilia as Selective Insulators of GPCR Cross-Talk

GPR88 Reveals a Discrete Function of Primary Cilia as Selective Insulators of GPCR Cross-Talk

Polymorphism of the COMT, MAO, DAT, NET and 5-HTT Genes, and Biogenic Amines in Parkinson’s Disease

Phenylethanolamine N-Methyltransferase Gene Polymorphisms and Adverse Outcomes in Acute Kidney Injury

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