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

The α_1A-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 α_1A-adrenoceptor than α_1A-adrenoceptors found in other parts of the body. This has led to the lower urinary tract α_1A-adrenoceptor being subclassified as an α_1L-adrenoceptor. It was demonstrated that this pharmacologically distinct α_1L-adrenoceptor is a product of the α_1A-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-HT_1B receptor. Alternatively, the influence of breast cancer resistance protein (BCRP) efflux transporters on the pharmacology of α_1A-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 https://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.