Signal transduction and regulation: Are all α1-adrenergic receptor subtypes created equal?

A selective alpha1D-adrenoreceptor antagonist inhibits human prostate cancer cell proliferation and motility “in vitro”

“…The multifaceted efficacy of the compound also in the absence of a stimulating effect by catecholamines suggests that A175 might behave as an inverse agonist of a receptor endowed with constitutive activity [3]; this action appears to be different from the neutral antagonist behavior we previously observed for this molecule in other functional tests [34]. As alpha1D-ARs display a prevalent intracellular localization [3,11,42,52], we wondered whether the effect of A175 might either the formation of homo/heterodimers [54], or the crosstalk with other membrane proteins, such as calcium channels [16].…”

“…As alpha1D-ARs display a prevalent intracellular localization [3,11,42,52], we wondered whether the effect of A175 might either the formation of homo/heterodimers [54], or the crosstalk with other membrane proteins, such as calcium channels [16]. As the majority of the studies on the relationship between alpha1D-AR activity and its cell localization have been conducted in transfected in vitro models [3,52,53], further studies should be undertaken to elucidate the functional role of the endogenous receptor and the mechanism(s) through which selective antagonists counteract its activity.…”

“…Alpha1-adrenoreceptors (alpha1-AR), which have been subdivided into three pharmacologically distinct subtypes (alpha1A, alpha1B and alpha1D, [3]), mediate several of the actions exerted by catecholamines on prostate cells, including stroma and epithelial growth, as well as smooth muscle contraction [4]. Increased sympathetic activity has been linked to PC recurrence, progression and aggressiveness (see [5] for references).…”

α1D-Adrenergic receptor insensitivity is associated with alterations in its expression and distribution in cultured vascular myocytes

“…To date, the clearest differences among the α 1 AR subtypes are in their subcellular localizations: α 1A -ARs and α 1B -ARs are primarily located at the plasma membrane while the majority of α 1D -ARs are found accumulated within the intracellular compartments of both recombinant and native cells [7][8][9][10] . Additionally, divergent factors or mechanisms have been found to differentially regulate the subtypes in regards of the receptor internalization/trafficking recycling, expression, and sensitivity of the signaling and effector molecules that they α 1D -Adrenergic receptor insensitivity is associated with alterations in its expression and distribution in cultured vascular myocytes 1586 www.nature.com/aps Fan LL et al Acta Pharmacologica Sinica npg are coupling, rendering a fine tuning for the α 1 -adrenergic responsiveness to different biological signals and for adapting cells to changes in the internal milieu and to overall homeostasis [2,6,[10][11][12] . Therefore, exploring the receptor characteristics of and regulatory mechanisms for each subtype is important for understanding and explicating their functional roles in both physiological and pathophysiological processes.…”

“…An increasing number of studies in vivo as well as in vitro have been performed to examine the cellular functions and regulatory mechanisms of α 1A -ARs and α 1B -ARs [2,6,[10][11][12] . Also, α 1D -ARs have been found to mediate contractile responses to catecholamines in several blood vessels with high potency [13,14] .…”