Disease relevance of ADRA1A

• The findings of the present study suggest that selective alpha 1c-adrenergic receptor antagonists may be clinically more efficacious and better tolerated agents for the treatment of symptomatic benign prostatic hyperplasia [1].
• CONCLUSIONS: Our findings suggest that the genetic variations in the ADRA1A gene are significantly associated with essential hypertension, and may play an important role in the development of essential hypertension in this Chinese population [2].
• Tamsulosin, a selective alpha 1A-adrenoceptor antagonist, has no clinically significant effect on blood pressure compared with placebo, thus posing less risk for the patient, especially with regard to symptomatic orthostatic hypotension [3].
• No evidence for association of alpha 1a adrenoceptor gene polymorphism and clozapine-induced urinary incontinence [4].

High impact information on ADRA1A

• A two-allele PstI RFLP for the alpha-1C adrenergic receptor gene (ADRA1C) [5].
• These results were confirmed by the observation that the C-terminal portion of PLC-beta 1, when co-expressed with the muscarinic acetylcholine receptor type 1 or the alpha 1C-adrenergic receptor in COS-7 cells, markedly inhibited ligand-induced release of inositol phosphates [6].
• We focused on one alpha(1)-adrenergic subtype, the alpha(1A)-adrenergic receptor, and proposed that genetic variants within the regulatory region of this gene (ADRA1A) alter the expression of this receptor, influencing susceptibility toward schizophrenia [7].
• Currently, three alpha 1AR subtypes have been characterized both pharmacologically and at the gene level: alpha 1aAR, alpha 1bAR, and alpha 1dAR [8].
• In several tissues from rat and cloned adrenoceptors, RS-17053 displayed high affinity for the alpha 1A-adrenoceptor (pKi and pA2 estimates of 9.1-9.9) and a 30-100-fold selectivity over the alpha 1B- and the alpha 1D-adrenoceptor subtypes (pK1 and pA2 estimates of 7.7-7.8) [9].

Chemical compound and disease context of ADRA1A

• PURPOSE: We evaluated the long-term (up to 6 years) safety and efficacy of the selective alpha 1A-adrenoceptor antagonist tamsulosin in patients with lower urinary tract symptoms associated with benign prostatic hyperplasia [10].

Biological context of ADRA1A

• We have cloned human alpha 1C-adrenergic receptor from human prostate cDNA library [11].
• Cloning, functional expression and tissue distribution of human cDNA for the alpha 1C-adrenergic receptor [11].
• The deduced amino acid sequence of the clone (P2C4) encodes a protein of 466 amino acids that showed strong sequence homology to the previously cloned bovine alpha 1C-adrenergic receptor [11].
• With reverse-transcription polymerase chain reaction assay, we observed alpha 1C-adrenergic receptor transcripts in heart, brain, liver and prostate, but not in kidney, lung, adrenal, aorta and pituitary [11].
• Two candidate genes stand out in these regions: the adrenergic receptor alpha 1C(1A) (ADRA1C) located on chromosome 8p and the adrenergic receptor alpha 2A (ADRA2A) located on chromosome 10q [12].

Anatomical context of ADRA1A

• CONCLUSIONS: To our knowledge, our study represents the first cellular localization of the alpha 1-adrenoceptor subtypes in the human prostate using highly selective alpha 1-adrenoceptor antagonists and is consistent with the physiological observation that the activity of prostatic smooth muscle is mediated by the alpha 1a-adrenoceptor [13].
• The radioligand binding properties of P2C4 expressed in COS-7 cells were very similar to those of bovine alpha 1C-adrenergic receptor [11].
• PATIENTS AND METHODS For 254 patients with BPH and/or lower urinary tract symptoms who received alpha(1)-adrenergic antagonists for > or = 3 months, the ADRA1A genotype at position 1475 of the coding region was determined [14].
• Likewise, the human neuronal SK-N-MC cell line, classically thought to express pharmacological alpha 1AAR and alpha 1BAR subtypes, expresses both alpha 1a/dAR and alpha 1cAR mRNA and no alpha 1bAR mRNA [15].
• 5. We have found that alpha 1a mRNA is predominant in the human vas deferens, and confirmed that contraction of this organ is mediated by the alpha 1A-adrenoceptor [16].

Associations of ADRA1A with chemical compounds

• KMD-3213, a novel, potent, alpha 1a-adrenoceptor-selective antagonist: characterization using recombinant human alpha 1-adrenoceptors and native tissues [17].
• RS-17053 (N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha, alpha-dimethyl-1H-indole-3-ethanamine hydrochloride), a selective alpha 1A-adrenoceptor antagonist, displays low affinity for functional alpha 1-adrenoceptors in human prostate: implications for adrenoceptor classification [9].
• As the expressed alpha 1c-adrenoceptor clone corresponds to the alpha 1A-adrenoceptor expressed in tissues, contraction of the human prostate to noradrenaline is therefore mediated by an alpha 1A-adrenoceptor [18].
• KMD-3213, a novel alpha 1A-adrenoceptor-selective antagonist, caused parallel rightward shifts of the concentration-response curves for l-phenylephrine [16].
• In contrast, WB 4101 an alpha 1A-adrenoceptor-selective ligand, displaced preferentially [125I]BE 2254 binding in the hilus and the CA3 region [19].

Other interactions of ADRA1A

• The design of new alpha 1-antagonists for BPH has concentrated on agents producing preferential blockage of urogenital vis-á-vis vascular alpha 1-adrenoceptors, based either on selectivity for the alpha 1A-adrenoceptor subtype or on functional uroselectivity in animal models [20].
• Compared to the alpha 1bAR, the alpha 1aAR has several more cis regulatory elements, suggesting more complex regulation [21].
• We examined the inheritance of polymorphisms in the ADRA2A and ADRA1C genes in 113 nuclear families identified through a GTS proband [12].
• This revised alpha 1a-adrenoceptor model accounts for direct interactions which are proposed between Ser 188 and Ser 192 and the meta and para hydroxyl groups of norepinephrine, respectively, in the G-protein coupled receptor state [22].

Analytical, diagnostic and therapeutic context of ADRA1A

• Tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist. A meta-analysis of two randomized, placebo-controlled, multicentre studies in patients with benign prostatic obstruction (symptomatic BPH). European Tamsulosin Study Group [23].

References