Two distinct
α1-adrenoceptor phenotypes (
α1A- and
α1L-ARs) are known to originate from a single ADRA1A(
α1a) gene by an as-yet-unknown mechanism. We hypothesized that an
α1a-AR–interacting protein could generate the
α1L-AR phenotype and we sought to identify such a protein and to examine its effects on the expression of
α1A and
α1L phenotypes. Cysteine-rich epidermal growth factor–like domain 1
α (CRELD1
α) was first identified using a yeast two-hybrid approach as an
α1a-AR–interacting protein. Transfection of
α1a-AR cDNA alone yielded Chinese hamster ovary (CHO) cells expressing
α1A-ARs having a predominant high affinity site for prazosin, with a low proportion (<10%) of prazosin-low affinity sites (
α1L-AR). Knockdown of endogenous CHO-CRELD1
α [
α1a-CKD(
α1A-enhanced) cells] enhanced the expression of
α1A-AR, whereas over-expression of CRELD1
α reduced
α1A-AR expression, yielding
α1a-COE(
α1L-dominant) cells expressing a high proportion (50%) of the
α1L-AR phenotype. The ligand binding and functional agonist and antagonist profiles in
α1a-CKD(
α1A-enhanced) and
α1a-COE(
α1L-dominant) cell lines were entirely in accord with the
α1A-AR and
α1L-AR phenotypes observed in intact tissues. CRELD1
α down-regulates expression of the
α1A-AR, thereby enhancing the proportion of expression of the
α1L-AR phenotype. The
α1L-AR–expressing
α1a-COE(
α1L-dominant) cell line reflects accurately the phenotype of this AR observed in vivo and will facilitate development of
α1L-AR–targeted drugs.
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