Human cloned α1A-adrenoceptor isoforms display α1L-adrenoceptor pharmacology in functional studies

Daniels, Donald V.; Gever, Joel R.; Jasper, Jeffrey R.; Kava, M. Shannon; Lesnick, John; Meloy, Trena D.; Stepan, George; Williams, Timothy J.; Clarke, David E.; Chang, David J.; Ford, Anthony

doi:10.1016/s0014-2999(99)00154-5

Cited by 75 publications

(63 citation statements)

References 11 publications

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“…12 When expressed in CHO-K1 cells, all 4 functional splice variants as well as the WT of the α 1a -AR display the pharmacological properties of so-called α 1L -AR. 13 This finding proves that the distinct pharmacology of α 1L -AR in human LUT is not a function of the differential tissue expression of α 1a -AR splice variants and it strongly supports the concept that the distinct α 1L pharmacology of the human LUT is not the result of tissue expression of a different α 1 -AR, but rather a functional conformation of α 1a -AR. To our knowledge the cellular events that may induce a shift between α 1a -AR high and low affinity states have not yet been elucidated.…”

Section: Splice Variants Of a 1a Receptorsupporting

confidence: 72%

COMBINED USE OF Α-Adrenergic AND MUSCARINIC ANTAGONISTS FOR THE TREATMENT OF VOIDING DYSFUNCTION

2005

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Purpose-We provide an overview of the medical literature supporting the combined use of muscarinic and α-adrenergic antagonist therapy for the treatment of voiding dysfunction. The MEDLINE database (1966 of the United States National Library of Medicine was searched for pertinent studies. Materials and Methods-Results-Although the mechanism of action of α-adrenergic antagonist therapy for voiding dysfunction has traditionally been assumed to be relaxation of the periurethral, prostatic and bladder neck smooth muscle, substantial evidence supports action at extraprostatic sites involved in micturition, including the bladder dome smooth muscle, peripheral ganglia, spinal cord and brain. Likewise the mechanism of action of anticholinergic therapy has been traditionally assumed to be inhibition of the M 3 muscarinic receptor subtypes that mediate normal bladder contractions. However, M 2 receptor mediates hypertrophied bladder contractions and there is evidence for an M 2 component to the suprasacral control of voiding.Conclusions-Based on the physiology of α-adrenergic and muscarinic receptors the inhibition of each one would be expected to be more beneficial than that of either alone because they would work on 2 components of detrusor function. Patients who would likely benefit from this combination therapy are men with lower urinary tract symptoms, women with urgency/frequency syndrome (overactive bladder), patients with uninhibited bladder contractions due to neurogenic bladder, and patients with pelvic pain and voiding symptoms, ie interstitial cystitis and chronic prostatitis/chronic pelvic pain syndrome. Keywordsbladder; prostate; adrenergic alpha-antagonists; muscarinic antagonists; urination disorders The wide range of patients who might benefit from this type of treatment combination is considered to be large, perhaps several times the estimated 17 million patients in the United States with overactive bladder. 1 A patent application has been filed for the treatment of lower urinary tract (LUT) symptoms (LUTS) in men with benign prostatic hyperplasia (BPH) with this combination. 2

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Section: Splice Variants Of a 1a Receptorsupporting

confidence: 72%

COMBINED USE OF Α-Adrenergic AND MUSCARINIC ANTAGONISTS FOR THE TREATMENT OF VOIDING DYSFUNCTION

2005

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“…Another pharmacologically distinct a 1 -adrenoceptor that mediates prostatic contraction has been suggested as a receptor with low anity for prazosin (a 1L -adrenoceptor) (Muramatsu et al, 1994); it may represent a functional phenotype of a 1a -adrenoceptor (Daniels et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Effects of castration on contraction and α₁‐adrenoceptor expression in rat prostate

Homma

Hamada

Nakayama³

et al. 2000

British J Pharmacology

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1 The prostate function is regulated by androgens and a-adrenergic activity. Clinically, antiandrogens and/or a 1 -adrenergic antagonists are commonly used to treat symptomatic prostatic hypertrophy. To elucidate the eects of androgen deprivation on prostate contractility via a 1 -adrenoceptor, the characteristics and expression of a 1 -adrenoceptors were examined in castrated rats. 2 Isolated prostate strips from intact and castrated rats were subjected to a phenylephrine stimulated contraction. Prazosin (10 nM), [ 3 H]-prazosin and phenoxybenzamine (3 ± 300 nM) were used for inhibition assay, receptor characterization and partial alkylation of a-adrenoceptor, respectively. The mRNA content of three subtypes of a-adrenoceptors was determined by reverse transcription combined with polymerase chain reaction (RT ± PCR). 3 Contractile response to phenylephrine increased in castrated rats, which could be explained by a relative increase of the stromal component. A lowered contraction potency was also noted in castrated rats. Receptor binding assay indicated minimal changes in the anity or density of a 1 -adrenoceptor. Escalating alkylation of the a 1 -adrenoceptor population resulted in a rightward shift in the contraction-response curves before depressing maximal contractile force, and the suppression was detected at lower doses in castrated rats. RT ± PCR study con®rmed the expression of three types of a 1 -adrenoceptor, a 1a , a 1b and a 1d -adrenoceptors, in intact rat prostate, and revealed that a 1a -adrenoceptor, but not a 1b or a 1d -adrenoceptors, was down-regulated in castrates. 4 The results show that androgen deprivation suppressed a 1 -adrenergic contractility of rat prostate strips, and the suppression was associated with down-regulation of receptor reserve for the a 1a -adreneroceptor population expressed in intact rat prostate.

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“…The identification of a minor proportion (less than 10%) of radioligand binding subsites using a mathematical analysis of the binding data may be unreliable (39). Notwithstanding, Ford et al reported a detectable amount of the α 1L -AR subtype expressed in their α 1L -AR-expressing CHO cell line (40,41). Thus, from our data, together with previously reported evidence, it appears that in a CHO cell background, the α 1L -AR phenotype can be found upon α 1a -AR transfection, although the α 1L -AR population is quite low when using the wildtype CHO cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of Cysteine-Rich Epidermal Growth Factor–Like Domain 1α (CRELD1α) as a Novel α1A-Adrenoceptor–Down-Regulating Protein and Establishment of an α1L-Adrenoceptor–Expressing Cell Line

et al. 2010

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Abstract. Two distinct α 1 -adrenoceptor phenotypes ( α 1A -and α 1L -ARs) are known to originate from a single ADRA1A( α 1a ) gene by an as-yet-unknown mechanism. We hypothesized that an α 1a -AR-interacting protein could generate the α 1L -AR phenotype and we sought to identify such a protein and to examine its effects on the expression of α 1A and α 1L phenotypes. Cysteine-rich epidermal growth factor-like domain 1 α (CRELD1 α ) was first identified using a yeast two-hybrid approach as an α 1a -AR-interacting protein. Transfection of α 1a -AR cDNA alone yielded Chinese hamster ovary (CHO) cells expressing α 1A -ARs having a predominant high affinity site for prazosin, with a low proportion (<10%) of prazosin-low affinity sites ( α 1L -AR). Knockdown of endogenous CHO-CRELD1 α [ α 1a -CKD( α 1A -enhanced) cells] enhanced the expression of α 1A -AR, whereas over-expression of CRELD1 α reduced α 1A -AR expression, yielding α 1a -COE( α 1L -dominant) cells expressing a high proportion (50%) of the α 1L -AR phenotype. The ligand binding and functional agonist and antagonist profiles in α 1a -CKD( α 1A -enhanced) and α 1a -COE( α 1L -dominant) cell lines were entirely in accord with the α 1A -AR and α 1L -AR phenotypes observed in intact tissues. CRELD1 α down-regulates expression of the α 1A -AR, thereby enhancing the proportion of expression of the α 1L -AR phenotype. The α 1L -AR-expressing α 1a -COE( α 1L -dominant) cell line reflects accurately the phenotype of this AR observed in vivo and will facilitate development of α 1L -AR-targeted drugs.

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Human cloned α1A-adrenoceptor isoforms display α1L-adrenoceptor pharmacology in functional studies

Cited by 75 publications

References 11 publications

COMBINED USE OF Α-Adrenergic AND MUSCARINIC ANTAGONISTS FOR THE TREATMENT OF VOIDING DYSFUNCTION

COMBINED USE OF Α-Adrenergic AND MUSCARINIC ANTAGONISTS FOR THE TREATMENT OF VOIDING DYSFUNCTION

Effects of castration on contraction and α₁‐adrenoceptor expression in rat prostate

Identification of Cysteine-Rich Epidermal Growth Factor–Like Domain 1α (CRELD1α) as a Novel α1A-Adrenoceptor–Down-Regulating Protein and Establishment of an α1L-Adrenoceptor–Expressing Cell Line

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Human cloned α1A-adrenoceptor isoforms display α1L-adrenoceptor pharmacology in functional studies

Cited by 75 publications

References 11 publications

COMBINED USE OF Α-Adrenergic AND MUSCARINIC ANTAGONISTS FOR THE TREATMENT OF VOIDING DYSFUNCTION

COMBINED USE OF Α-Adrenergic AND MUSCARINIC ANTAGONISTS FOR THE TREATMENT OF VOIDING DYSFUNCTION

Effects of castration on contraction and α1‐adrenoceptor expression in rat prostate

Identification of Cysteine-Rich Epidermal Growth Factor–Like Domain 1α (CRELD1α) as a Novel α1A-Adrenoceptor–Down-Regulating Protein and Establishment of an α1L-Adrenoceptor–Expressing Cell Line

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Effects of castration on contraction and α₁‐adrenoceptor expression in rat prostate