What makes the α_1A‐adrenoceptor gene product assume an α_1L‐adrenoceptor phenotype?

Abstract

The α1A‐adrenoceptor is abundantly expressed in the lower urinary tract and is the principal therapeutic target for the symptomatic treatment of lower urinary tract symptoms in men. Prazosin has a lower affinity for the lower urinary tract α1A‐adrenoceptor than α1A‐adrenoceptors found in other parts of the body. This has led to the lower urinary tract α1A‐adrenoceptor being subclassified as an α1L‐adrenoceptor. It was demonstrated that this pharmacologically distinct α1L‐adrenoceptor is a product of the α1A‐adrenoceptor gene, but the mechanism by which this altered phenotype is achieved remains a mystery. Hypotheses for this altered pharmacology include the presence of an interacting protein such as cysteine‐rich with EGF‐like domain (CRELD) 1 or other GPCRs such as the CXCR2 chemokine or 5‐HT1B receptor. Alternatively, the influence of breast cancer resistance protein (BCRP) efflux transporters on the pharmacology of α1A‐adrenoceptors has also been investigated. These and other hypotheses will be described and discussed in this review. Linked Articles This article is part of a themed section on Adrenoceptors—New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc

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“…Prazosin was found to have lower affinity to lower urinary tract α1A-adrenoceptors than α1-adrenoceptors in other systems of the body, and thus this particular sub-classification of α1A-adrenoceptors in the lower urinary tract have been named α1L-arenorecptors. While pharmacologically distinct, α1L-adrenoceptors are products of the α1-adrenoceptor gene, but its altered phenotype is still under investigation [ 23 ].…”

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“…The clone originally called α1C-AR corresponds to the pharmacologically defined α1A-AR [ 11 ]. Some tissues possess α1A-ARs that display a relatively low affinity in binding assays for prazosin (the α1-AR antagonist) and are termed α1L-ARs, but recent evidence suggests that they are a phenotypic (conformational) state of α1A-ARs, rather than a distinct entity [ 12 , 13 , 14 , 15 ].…”

Adrenoceptors—New roles for old players

“…It has long puzzled us that some functions apparently mediated by an α 1 ‐adrenoceptor exhibited only a low affinity for prazosin and other quinazolines and were termed α 1L . While it is now clear that the α 1A ‐adrenoceptor gene is responsible for the α 1L phenotype, it remains controversial which factors make this gene product assume states that are associated with high and low affinity for prazosin in a cell type‐dependent manner (White, da Silva Junior, Lim, & Ventura, ). Hypotheses that have been put forward to explain this include the presence of interacting proteins such as CRELD1 (cysteine‐rich with epidermal growth factor‐like domain) or the presence of efflux transporters such as BCRP (breast cancer resistance protein; also ABCG2), but none of them is entirely convincing, and the search for additional or alternative explanations remains ongoing.…”