Pharmacological pleiotropism of the human recombinant alpha1A-adrenoceptor: implications for alpha1-adrenoceptor classification

Br J Pharmacol. 1997 Jul;121(6):1127-35. doi: 10.1038/sj.bjp.0701207.

Abstract

1. Three fully-defined alpha1-adrenoceptors (alpha1A, alpha1B and alpha1D) have been established in pharmacological and molecular studies. A fourth alpha1-adrenoceptor, the putative alpha1L-adrenoceptor, has been defined in functional but not molecular studies, and has been proposed to mediate contraction of human lower urinary tract tissues; its relationship to the three fully characterized alpha1-adrenoceptors is not known. 2. In the present study, binding affinities were estimated by displacement of [3H]-prazosin in membrane homogenates of Chinese hamster ovary (CHO-K1) cells stably expressing the human alpha1A-, alpha1B- and alpha1D-adrenoceptors and were compared with affinity estimates obtained functionally in identical cells by measuring inhibition of noradrenaline (NA)-stimulated accumulation of [3H]-inositol phosphates. 3. For the alpha1A-adrenoceptor, binding studies revealed a pharmacological profile typical for the classically defined alpha1A-adrenoceptor, such that prazosin, RS-17053, WB 4101, 5-methylurapidil, Rec 15/2739 and S-niguldipine all displayed subnanomolar affinity. A different profile of affinity estimates was obtained in inositol phosphates accumulation studies: prazosin, WB 4101, 5-methylurapidil, RS-17053 and S-niguldipine showed 10 to 40 fold lower affinity than in membrane binding. However, affinity estimates were not 'frameshifted', as tamsulosin, indoramin and Rec 15/2739 yielded similar, high affinity estimates in binding and functional assays. 4. In contrast, results from human alpha1B- and alpha1D-adrenoceptors expressed in CHO-K1 cells gave antagonist affinity profiles in binding and functional assays that were essentially identical. 5. A concordance of affinity estimates from the functional (inositol phosphates accumulation) studies of the alpha1A-adrenoceptor in CHO-K1 cells was found with estimates published recently from contractile studies in human lower urinary tract tissues (putative alpha1L-adrenoceptor). These data show that upon functional pharmacological analysis, the cloned alpha1A-adrenoceptor displays pharmacological recognition properties consistent with those of the putative alpha1L-adrenoceptor. Why this profile differs from that obtained in membrane binding, and whether it explains the alpha1L-adrenoceptor pharmacology observed in many native tissues, requires further investigation.

MeSH terms

  • Adrenergic Agents / metabolism
  • Adrenergic Agents / pharmacology
  • Animals
  • CHO Cells
  • Cloning, Molecular
  • Cricetinae
  • Humans
  • Inositol Phosphates / metabolism
  • Radioligand Assay
  • Receptors, Adrenergic, alpha-1 / classification*
  • Receptors, Adrenergic, alpha-1 / drug effects*
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Recombinant Proteins / classification
  • Recombinant Proteins / drug effects
  • Recombinant Proteins / metabolism

Substances

  • ADRA1A protein, human
  • Adrenergic Agents
  • Inositol Phosphates
  • Receptors, Adrenergic, alpha-1
  • Recombinant Proteins