A novel nonneuronal catecholaminergic system: exocrine pancreas synthesizes and releases dopamine.

Mezey, Éva; Eisenhofer, Graeme; Harta, G; Hansson, Stefan R.; Gould, Lydia; Hunyady, Béla; Hoffman, Beth J.

doi:10.1073/pnas.93.19.10377

Cited by 115 publications

(73 citation statements)

References 36 publications

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“…However, loss of D1r could be rescued by one D2r allele only in animals fed a semiliquid diet, suggesting a preponderant D1r-mediated role in the control of GI activity. Interestingly, another DA receptor, D5r, is also expressed in the GI mucosa and suggested to mediate cytoprotective effects (41,44,45). This expression suggests that D5r might compensate for loss of D1r in the presence of D2r-mediated signaling but is unable to compensate for loss of both receptor-mediated functions.…”

Section: Discussionmentioning

confidence: 99%

Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice

Kobayashi

Iaccarino

Saiardi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Dopamine (DA) controls a wide variety of physiological functions in the central nervous system as well as in the neuroendocrine and gastrointestinal systems. DA signaling is mediated by five cloned receptors named D1-D5. Knockout mouse models for the five receptors have been generated, and, albeit impaired for some important DA-mediated functions, they are viable and can reproduce. D1 and D2 receptors are the most abundant and widely expressed DA receptors. Cooperative͞synergistic effects mediated by these receptors have been suggested, in particular, in the control of motor behaviors. To analyze the extent of such interrelationship, we have generated double D1͞D2 receptor mutants. Interestingly, in contrast to single knockouts, we found that concurrent ablation of the D1 and D2 receptors is lethal during the second or third week after birth. This dramatic phenotype is likely to be related to altered feeding behavior and dysfunction of the gastrointestinal system, especially because major anatomical changes were not identified in the brain. Similarly, in the absence of functional D1, heterozygous D2 mutants (D1r ؊/؊ ;D2r ؉/؊ ) showed severe growth retardation and did not survive their postweaning period. The analysis of motor behavior in D1r͞D2r compound mutants showed that loss of D2-mediated functions reduces motor abilities, whereas the effect of D1r ablation on locomotion strongly depends on the experimental paradigms used. These studies highlight the interrelationship between D1 and D2 receptor-mediated control of motor activity, food intake, and gastrointestinal functions, which has been elusive in the singlegene ablation studies.knockout mice ͉ motor function ͉ feeding behavior ͉ gastrointestinal system T he diverse physiological functions of dopamine (DA) are mediated by five distinct receptors, which by structural and pharmacological means have been grouped into two families: the D1-like and D2-like receptors. The D1-like family comprises the D1 and D5 receptors, whereas D2, D3, and D4 receptors form the D2-like family. Pharmacological studies have not allowed a full understanding of the specific role of each DA receptor in vivo because of the lack of ligands with absolute receptor specificity. Knockout mice for each DA receptor have now been reported (1-9), substantially increasing our knowledge of the dopaminergic system (10, 11).Among DA receptors the most widely and abundantly expressed in the central nervous system are the D1 and D2 receptors, whereas D3, D4, and D5 have lower abundance and a very restricted localization. Mutation of the D1 gene (D1r) in mice resulted in growth retardation, failure to respond to the motor stimulant effects of addictive drugs, and poor learning performance (2,3,(12)(13)(14). Moderate growth retardation was also reported in mice lacking D2 receptors (D2r Ϫ/Ϫ ), which in addition are hypoactive, fail to experience the rewarding properties of morphine, and lose DA autoreceptor function (4, 15, 16).Importantly, neuroanatomical as well as pharmacological studies have pro...

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Section: Discussionmentioning

confidence: 99%

Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice

Kobayashi

Iaccarino

Saiardi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…15 In addition to these central nervous system sites, transient expression of TH occurs in the developing heart, in cells destined to become pacemaker, and in cells of the conducting system. 28 Expression of TH has also been reported in cells of the exocrine pancreas 29 ; non-neuronal, possibly immune cells of the duodenum 30 ; T lymphocytes 31,32 ; adipocytes 33 ; and skin keratinocytes. 34 The association of each of these cell types with AT 1A R expression has not been examined, and the role of Ang II and AT 1A R in these cells in the angiotensin-induced hypertensive response is beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Angiotensin Type 1A Receptors on Catecholaminergic Cells Contributes to Angiotensin-Dependent Hypertension

et al. 2013

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H ypertension is a key contributor to multiple cardiovascular diseases and thus to the principal cause of morbidity and mortality worldwide.1 The renin-angiotensin system plays a pivotal role in the regulation of blood pressure (BP) through effects on fluid and electrolyte homeostasis, vascular constriction, and modulation of the autonomic nervous system.2 Overactivity of this system is implicated in the development and maintenance of hypertension, and antagonists of the angiotensin II (Ang II) type 1 receptor (AT 1 R) are a first-line option for treating hypertension.Altered handling of fluid and electrolytes by the kidney plays an important part in hypertension, 3,4 and part of the hypertensive response to Ang II is reliant on the expression of AT 1 R within the proximal tubule of the kidney. 5,6 However, mice lacking the Ang II type 1A receptor (AT 1A R) in the kidney show a partial hypertensive response to Ang II infusion, 7 suggesting that AT 1 R in other regions plays a role.Elevated sympathetic activity is observed in hypertensive people and experimental models of hypertension, [8][9][10][11] and approaches to reduce this, such as renal nerve denervation, are effective antihypertensive therapies. 10Studies in experimental animals and humans show a strong correlation between the distribution of AT 1 R and central and peripheral cells of the sympathetic nervous system. Sympathetic postganglionic neurons, including adrenal medullary chromaffin cells, express AT 1 R and are stimulated by Ang II.12 Through presynaptic receptors, Ang II potentiates the release of noradrenaline from sympathetic nerve terminals. 13 Many catecholamine-synthesizing neurons in sympathetic premotor regions of the brain, including the rostral ventrolateral medulla (RVLM), express AT 1 R. [14][15][16] Given this interaction between AT 1 R-expressing catecholaminergic cells and the involvement of both the angiotensin and sympathetic systems in the development and maintenance of hypertension, we hypothesized that the deletion of AT 1 R from catecholaminergic cells would affect both basal BP and the development of hypertension in response to infusion of Ang II. This hypothesis was tested in a transgenic mouse model using Abstract-Hypertension contributes to multiple forms of cardiovascular disease and thus morbidity and mortality. The mechanisms inducing hypertension remain unclear although the involvement of homeostatic systems, such as the renin-angiotensin and sympathetic nervous systems, is established. A pivotal role of the angiotensin type 1 receptor in the proximal tubule of the kidney for the development of experimental hypertension is established. Yet, other systems are involved. This study tests whether the expression of angiotensin type 1A receptors in catecholaminergic cells contributes to hypertension development. Using a Cre-lox approach, we deleted the angiotensin type 1A receptor from all catecholaminergic cells. This deletion did not alter basal metabolism or blood pressure but delayed the onset of angiotensindepe...

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“…Although the detection of catecholaminesynthesizing cells in the ovary was initially surprising (14,16), it is now clear that other nonneuronal tissues are endowed with similar systems. Thus, an intrinsic adrenergic cell system has been identified recently in the heart (33), and nonneuronal DA-producing cells have been found in the exocrine pancreas (34), suggesting that the distribution of intrinsic catecholaminergic systems is widespread and of importance for the local regulation of tissue functions.…”

Section: Discussionmentioning

confidence: 99%

Oocytes are a source of catecholamines in the primate ovary: Evidence for a cell–cell regulatory loop

Mayerhofer

Smith

Danilchik

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Catecholamines, thought to derive from the extrinsic innervation of the ovary, participate in the regulation of ovarian development and mature gonadal function. Recently, intraovarian neurons containing tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, were described in the ovary of nonhuman primates. We now show that the primate ovary expresses both the genes encoding TH and dopamine ␤-hydroxylase (DBH), the key enzymes in norepinephrine (NE) biosynthesis. Ovarian neurons were identified as a site of TH and DBH gene expression, and surprisingly, oocytes were identified as an exclusive site of DBH synthesis. Oocytes contain neither TH mRNA nor protein, indicating that they are unable to synthesize dopamine (DA). They did, however, express a DA transporter gene identical to that found in human brain. The physiological relevance of this transporter system and DBH in oocytes was indicated by the ability of isolated oocytes to metabolize exogenous DA into NE. Isolated follicles containing oocytes-but not those from which the oocytes had been removed-responded to DA with an elevation in cAMP levels; this elevation was prevented by propranolol, a ␤-adrenoreceptor antagonist. The results suggest that oocytes and somatic cells are linked by a neuroendocrine loop consisting of NE synthesized in oocytes from actively transported DA and cAMP produced by somatic follicular cells in response to NE-induced ␤-adrenoreceptor activation.All three major catecholamines used as transmitters by sympathetic neurons of the peripheral nervous system are present in the mammalian ovary (1, 2). Among them, norepinephrine (NE) is the most abundant (1, 3, 4). A variety of experimental approaches have demonstrated that NE, recognized by specific receptors of the ␤ 2 -adrenergic subtype, stimulates ovarian steroidogenesis on its own and facilitates the stimulatory effect of gonadotropins on steroid production (5-7). NE also promotes follicular development (8-10). In contrast to this body of information, very little is known about the potential contribution(s) of dopamine (DA) to ovarian physiology. In one of the few studies on the subject (11), a stimulatory effect of DA on human granulosa cell steroidogenesis was blocked by propranolol, a ␤-adrenoreceptor antagonist, indicating that the effect of the catecholamine was indirect and most likely mediated by NE.It is commonly assumed that catecholamines reach the ovary exclusively via its extrinsic sympathetic innervation (12). However, ovarian denervation reduces, but does not eliminate, the content of NE in the gland (13), implying the existence of an additional source of catecholamine synthesis. That this source may be intrinsic to the ovary has been suggested by the identification of neuronal cell bodies containing immunoreactive tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, in the ovary of nonhuman primates (14). Whether this is the only, or the more important, intragonadal source of catecholamines in the primate ...

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A novel nonneuronal catecholaminergic system: exocrine pancreas synthesizes and releases dopamine.

Cited by 115 publications

References 36 publications

Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice

Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice

Stimulation of Angiotensin Type 1A Receptors on Catecholaminergic Cells Contributes to Angiotensin-Dependent Hypertension

Oocytes are a source of catecholamines in the primate ovary: Evidence for a cell–cell regulatory loop

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