Disease relevance of Adra2a

• Both low- and high-frequency regulation seem to be physiologically important, as mice lacking both alpha2A- and alpha2C-receptor subtypes have elevated plasma noradrenaline concentrations and develop cardiac hypertrophy with decreased left ventricular contractility by four months of age [1].
• Pretreatment with pertussis toxin abolished the effect of UK 14,304 also in cultures from alpha2A/DKO mice [2].
• Recent studies with gene-targeted mice have revealed that the alpha2A-AR has a major role in the mediation of many prominent effects of subtype non-selective alpha2-AR agonists, i.e. sedation, analgesia, hypothermia, sympatho-inhibition, and reduction of blood pressure [3].
• Excess mortality in alpha2A- and alpha2C-KO strains was attributable to heart failure with enhanced left ventricular hypertrophy and fibrosis and elevated circulating catecholamines [4].
• Reduced thrombus stability in mice lacking the alpha2A-adrenergic receptor [5].

Psychiatry related information on Adra2a

• This detrimental effect was prevented by pretreatment with the alpha2-antagonist yohimbine (1-3 mg kg(-1) i.p.) and by the alpha2A-antagonist BRL-44408 (0.3-1 mg kg(-1) i.p.). By contrast, the alpha(2B,C) antagonists ARC-239 (10 mg kg(-1) i.p.) and prazosin (1 mg kg(-1) i.p.) did not revert the amnesia induced by both clonidine and guanabenz [6].

High impact information on Adra2a

• Alpha2-adrenergic receptors are known to have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system; however, the individual roles of the three highly homologous alpha2-adrenergic-receptor subtypes (alpha2A, alpha2B, alpha2C) in this process are not known [1].
• Our results show that the alpha 1 and alpha 2A domains of the H-2Kk antigen can constitute target molecules for alloimmune anti-Kk T cells, whereas the alpha 2B region, when exchanged for Kd or Kb sequences, plays only a limited role [7].
• In contrast, the alpha 1 and alpha 2A domains of Kd are not sufficient to be recognized by alloimmune anti-Kd T cells [7].
• A point mutation (D79N) of the alpha2A adrenergic receptor abolishes the antiepileptogenic action of endogenous norepinephrine [8].
• Gene targeting was used to introduce a point mutation into the alpha2A adrenergic subtype in the mouse genome [8].

Biological context of Adra2a

• The alpha 2AAR subtype appears to mediate reduction in blood pressure following alpha 2A agonist administration as well as sedative, anesthetic-sparing, and analgesic responses to alpha 2AAR agonists [9].
• Distribution of mRNA encoding three alpha 2-adrenergic receptor subtypes in the developing mouse embryo suggests a role for the alpha 2A subtype in apoptosis [10].
• Although the spatial expression of the transgene in the adult brain often overlaps that for the endogenous alpha 2A adrenergic receptor, both ectopic expression and the absence of appropriate expression were noted; in contrast five of the six lines show temporal expression characteristic of the endogenous alpha 2A adrenergic receptor gene [11].
• The alpha-subunit of eukaryotic initiation factor 2B (eIF-2B), a guanine nucleotide exchange protein that functions in regulation of translation, was observed to associate with the carboxyl-terminal cytoplasmic domains of the alpha2A- and alpha2B-adrenergic receptors in a yeast two-hybrid screen of a cDNA library prepared from 293 cells [12].
• Activation and deactivation kinetics of alpha 2A- and alpha 2C-adrenergic receptor-activated G protein-activated inwardly rectifying K+ channel currents [13].

Anatomical context of Adra2a

• Similar chloroethylclonidine treatment (10 microM, 20 min at 37 degrees) reduced the number of detectable alpha 2-adrenoceptors in cell lines transfected with the alpha 2-C10 or alpha 2-C4 gene but not in those transfected with alpha 2-C2 adrenoceptors [14].
• The maximal inhibition of vas deferens contraction by the alpha2 agonist in alpha2A-AR knockout mice was only 42 +/- 9% [15].
• Abnormal regulation of the sympathetic nervous system in alpha2A-adrenergic receptor knockout mice [15].
• The mRNA encoding the alpha 2A-AR subtype shows both the earliest and the most widespread expression pattern, including developing stomach and cecum, many craniofacial regions and areas in the central nervous system [10].
• Both alpha 2A and alpha 2C adrenergic receptor messenger RNA demonstrate strong expression in the amygdaloid complex, hypothalamus, olfactory system and the hippocampal formation [11].

Associations of Adra2a with chemical compounds

• We conclude that chloroethylclonidine binds to all major alpha-adrenoceptor subtypes and irreversibly inactivates not only alpha 1B-adrenoceptors but also alpha 2A- and alpha 2C-adrenoceptors, whereas alpha 1A- and alpha 2B-adrenoceptors are relatively resistant to its alkylating action, although they can bind chloroethylclonidine [14].
• Previous studies demonstrated that mutation of a conserved aspartate residue in the alpha 2AAR to asparagine (D79N alpha 2AAR) resulted in a receptor that retained its ability to inhibit voltage-gated Ca2+ channels and cAMP production but was unable to activate K+ currents in AtT20 cells (Surprenant et al., 1992) [9].
• RESULTS: In vivo, loss and recovery of the righting reflex required similar times after intraperitoneal injection of etomidate in wild-type and in alpha2A-receptor-deficient mice, indicating that the hypnotic effect of etomidate in mice does not require the alpha2A-receptor subtype [16].
• Little autoinhibition by released noradrenaline in trains of pulses remains when the alpha2 A/D-adrenoceptor is lacking, again in accord with a predominance of alpha2 A/D-autoreceptors [17].
• Dexmedetomidine produces its neuroprotective effect via the alpha 2A-adrenoceptor subtype [18].

Regulatory relationships of Adra2a

• Stimulation of alpha 2B receptors in vascular smooth muscle produces hypertension and counteracts the clinically beneficial hypotensive effect of stimulating alpha 2A receptors in the central nervous system [19].
• Norepinephrine transporter knockout-induced up-regulation of brain alpha2A/C-adrenergic receptors [20].

Other interactions of Adra2a

• Expression levels of Adra2a and Adra2b mRNA in brain and kidney are not altered by the Adra2c knockout [21].
• Agonist activation regulates reciprocal interactions of spinophilin and arrestin with the alpha2A- and alpha2B -adrenergic receptor (AR) subtypes via their 3i loop [22].
• Therefore, the effect of testosterone, 17 beta-estradiol, progesterone, and norepinephrine (NE) on adrenergic receptor (AR) gene expression (alpha 2A-, beta 1-, -, and beta 3-AR) and lipolytic activity was investigated in differentiated brown adipocytes in culture [23].
• Adra2r (alpha 2-C10) and Adrb1r (beta 1) receptors mapped to the distal region of mouse chromosome 19 [24].
• Development of agents that promote selective activation of the alpha2A receptor subtype may provide novel therapeutic strategies for the prophylaxis of epilepsy [8].

Analytical, diagnostic and therapeutic context of Adra2a

• Substitution of a mutant alpha2a-adrenergic receptor via "hit and run" gene targeting reveals the role of this subtype in sedative, analgesic, and anesthetic-sparing responses in vivo [25].
• Which of the three alpha2-adrenoceptor subtypes of alpha2A, alpha2B, or alpha2C mediates the neuroprotective effect of dexmedetomidine was examined in cell culture as well as in an in vivo model of neonatal asphyxia [18].
• Site-directed mutagenesis of non-conserved amino acids in the second intracellular loop of the alpha2A subtype indicated that several residues are involved in the coupling specificity [26].
• Transcutaneous electrical nerve stimulation activates peripherally located alpha-2A adrenergic receptors [27].
• In situ hybridization revealed expression of both alpha 2A and alpha 2B mRNAs in the prenatal rat brain, suggesting that these variant proteins may have a role in synaptogenesis [28].

References