Gene targeting — homing in on α2-adrenoceptor-subtype function

MacDonald, Ewen; Kobilka, Brian K.; Scheinin, Mika

doi:10.1016/s0165-6147(97)90625-8

Cited by 233 publications

(101 citation statements)

References 35 publications

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“…However, the L-659,066-sensitive fraction of the response to m -nitrobiphenyline was likely to be mediated through VSMC α 2C AR, since this α 2C -selective agonist also acted as an α 2A+B AR-antagonist (Crassous et al, 2007). Although VSMC α 2C AR did not contribute to BP control in genetically modified mice (MacDonald et al, 1997), stimulated α 2C AR-mediated vasoconstriction has been demonstrated in veins and arterioles (Chotani et al, 2004; Görnemann et al, 2007). The L-659,066-insensitive part of the agonist-induced vasoconstriction was likely to be mediated through α 1 AR, since at least fadolmidine contained α 1 AR-agonistic activity (Lehtimaki et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin AT1 – α2C-Adrenoceptor Interaction Disturbs α2A-auto-Inhibition of Catecholamine Release in Hypertensive Rats

Berg¹

2013

Front. Neurol.

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α2-Adrenoceptors lower central sympathetic output and peripheral catecholamine release, and thus may prevent sympathetic hyperactivity and hypertension. α2AR also influence vascular tension. These α2AR are malfunctioning in spontaneously hypertensive rats (SHR). Here I tested if an interaction between α2AR subtypes and the angiotensin AT1 receptor (AT1R) precipitated these disorders. Blood pressure was monitored through a femoral artery catheter and cardiac output by ascending aorta flow in anesthetized rats. Catecholamine concentrations were determined in plasma collected at the end of a 15-min tyramine-infusion. Tyramine stimulates norepinephrine release through the re-uptake transporter, thus preventing re-uptake. Presynaptic control of vesicular release is therefore reflected as differences in overflow to plasma. Previous experiments showed surgical stress to activate some secretion of epinephrine, also subjected to α2AR-auto-inhibition. Normotensive rats (WKY) and SHR were pre-treated with (1) vehicle or α2AR-antagonist (L-659,066), followed by fadolmidine (α2C>B>A + α1AR-agonist), ST-91 (α2non-A-selective agonist), or m-nitrobiphenyline (α2CAR-agonist + α2A+B-antagonist), or (2) AT1R-antagonist losartan, losartan + L-659,066, or losartan + clonidine. In WKY, L-659,066 alone, L-659,066 + agonist or losartan + L-659,066 increased catecholamine overflow to plasma after tyramine and eliminated the norepinephrine-induced rise in total peripheral vascular resistance (TPR). In SHR, L-659,066 + fadolmidine/ST-91/m-nitrobiphenyline and losartan + L-659,066 greatly increased, and losartan + clonidine reduced, catecholamine concentrations, and L-659,066 + ST-91, losartan + L-659,066 and losartan + clonidine eliminated the tyramine-induced rise in TPR. Separately, these drugs had no effect in SHR. In conclusion, peripheral α2CAR-stimulation or AT1R-inhibition restored failing α2AAR-mediated auto-inhibition of norepinephrine and epinephrine release and control of TPR in SHR.

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Section: Discussionmentioning

confidence: 99%

Angiotensin AT1 – α2C-Adrenoceptor Interaction Disturbs α2A-auto-Inhibition of Catecholamine Release in Hypertensive Rats

Berg¹

2013

Front. Neurol.

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“…However, certain types of adrenoceptors, such as β 1 ‐, α 2A ‐, and α 2C ‐adrenoceptors are expressed in the striatum (Nicholas et al. 1996; MacDonald et al. 1997).…”

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confidence: 99%

“…1991). α 2A ‐Adrenoceptors are widely distributed in the brain including the striatum (MacDonald et al. 1997), and mediate the inhibition of monoamine release and metabolism (Trendelenburg et al.…”

mentioning

confidence: 99%

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Role of adrenoceptors in the regulation of dopamine/DARPP‐32 signaling in neostriatal neurons

Hara

Fukui

Hieda

et al. 2010

Journal of Neurochemistry

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J. Neurochem. (2010) 113, 1046–1059. Abstract Studies in animal models of Parkinson’s disease have revealed that degeneration of noradrenaline neurons is involved in the motor deficits. Several types of adrenoceptors are highly expressed in neostriatal neurons. However, the selective actions of these receptors on striatal signaling pathways have not been characterized. In this study, we investigated the role of adrenoceptors in the regulation of dopamine/dopamine‐ and cAMP‐regulated phosphoprotein of Mr 32 kDa (DARPP‐32) signaling by analyzing DARPP‐32 phosphorylation at Thr34 [protein kinase A (PKA)‐site] in mouse neostriatal slices. Activation of β1‐adrenoceptors induced a rapid and transient increase in DARPP‐32 phosphorylation. Activation of α2‐adrenoceptors also induced a rapid and transient increase in DARPP‐32 phosphorylation, which subsequently decreased below basal levels. In addition, activation of α2‐adrenoceptors attenuated, and blockade of α2‐adrenoceptors enhanced dopamine D1 and adenosine A2A receptor/DARPP‐32 signaling. Chemical lesioning of noradrenergic neurons mimicked the effects of α2‐adrenoceptor blockade. Under conditions of α2‐adrenoceptor blockade, the dopamine D2 receptor‐induced decrease in DARPP‐32 phosphorylation was attenuated. Our data demonstrate that β1‐ and α2‐adrenoceptors regulate DARPP‐32 phosphorylation in neostriatal neurons. Gi activation by α2‐adrenoceptors antagonizes Gs/PKA signaling mediated by D1 and A2A receptors in striatonigral and striatopallidal neurons, respectively, and thereby enhances D2 receptor/Gi signaling in striatopallidal neurons. α2‐Adrenoceptors may therefore be a therapeutic target for the treatment of Parkinson’s disease.

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“…2000). The decreased HR mainly reflects the baroreceptor reflex response to alpha‐2B receptor‐mediated vasoconstriction (MacDonald et al 1997). HR similar to or slightly higher than these have been reported in arctic foxes anaesthetized with xylazine‐ketamine and medetomidine‐ketamine (Jalanka 1990; Fuglei et al.…”

Section: Discussionmentioning

confidence: 99%

A comparison of the efficacy and cardiorespiratory effects of four medetomidine-based anaesthetic protocols in the red fox (Vulpes vulpes)

Bertelsen

Villadsen

2009

Veterinary Anaesthesia and Analgesia

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Gene targeting — homing in on α2-adrenoceptor-subtype function

Cited by 233 publications

References 35 publications

Angiotensin AT1 – α2C-Adrenoceptor Interaction Disturbs α2A-auto-Inhibition of Catecholamine Release in Hypertensive Rats

Angiotensin AT1 – α2C-Adrenoceptor Interaction Disturbs α2A-auto-Inhibition of Catecholamine Release in Hypertensive Rats

Role of adrenoceptors in the regulation of dopamine/DARPP‐32 signaling in neostriatal neurons

A comparison of the efficacy and cardiorespiratory effects of four medetomidine-based anaesthetic protocols in the red fox (Vulpes vulpes)

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