Prostatic α1‐adrenoceptors: New concepts of function, regulation, and intracellular signaling

Abstract

Prostatic α1 -adrenoceptors are known to be involved in the pathophysiology of lower urinary tract symptoms (LUTS) in patients with benign prostate obstruction (BPO). It is widely accepted that enhanced α1 -adrenergic smooth muscle contraction can contribute to bladder outlet obstruction; α1 -adrenoceptor antagonists still represent a gold standard in the treatment of LUTS. Accordingly, expression and function of α1 -adrenoceptors in the prostate have attracted large attention over the last three decades. However, recent preclinical studies have challenged our understanding of prostatic α1 -adrenoceptors. In the current review article, we summarize "modern" concepts of prostatic α1 -adrenoceptors which include novel intracellular mediators of contraction as well as non-contractile signaling and post-translational receptor regulation. Configuration of α1 -adrenoceptors with binding partners may determine its function, leading to a dynamic receptor with high functional plasticity. Cooperative regulation of different intracellular effectors (MAPK, Akt, transcription factors) by α1 -adrenoceptors, hormones or growth factors has been suggested. The prostatic α1 -adrenoceptor is no longer being regarded as an isolated, static receptor exclusively mediating prostatic smooth muscle contraction by G proteins, but a dynamic receptor interacting with other receptors within a complex network of mediators.

Cooperative effects of EGF, FGF, and TGF-β1 in prostate stromal cells are different from responses to single growth factors

“…BPH is often associated with prostate enlargement, which may cause benign prostate obstruction (BPO) and voiding symptoms [2,21]. Despite its high prevalence and its relevance for pathophysiology and therapy of LUTS, development of BPH is poorly understood [8].…”

“…Stromal growth is critical for benign prostatic hyperplasia (BPH) and prostate enlargement, which are related with development of lower urinary tract symptoms (LUTS) in considerable parts of the elderly male population in Western countries [1,2]. Prostate growth and development of BPH require a variety of humoral and paracrine factors, including different growth factors [1].…”

“…However, it appears likely that different growth factors may act at once in vivo. In fact, it has been proposed, that a network of factors working cooperatively together, rather than a single "key factor" determines prostate growth and BPH [2,5,7]. In the non-malignant human prostate, FGF and TGF-β1 are produced by the stromal smooth muscle cells, and additionally secreted by epithelial cells of glands [7,8,12].…”

The Role of Inflammation in Lower Urinary Tract Symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH) and Its Potential Impact on Medical Therapy

“…Therefore, infiltrating lymphocytes (inflammation condition) can maintain tissue proliferation also in the presence of 5α reductase inhibitors. Interestingly, proliferation and hypoxia can stimulate ROS production, further supporting a vicious circle contraction [15,16]. Thus, a1-adrenoceptors and the TXA2-R share common intracellular mediators to induce smooth muscle contraction in the prostate.…”

Cooperative Interaction between the Alpha1-Adrenoceptors (α1-AR) and Transient Receptor Potential (TRP) Triggers a Proliferative Cell Signal in Prostate Cancer Cell Lines

“…They are linked to the heterotrimeric G protein containing the Gαq/11/14/16 subunits that activates phospholipase C (PLC) and promotes the cleavage of inositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3); DAG and IP3 then promote the activation of protein kinase C (PKC). Evidence suggests the α1-ARs contribute in the catecholamines-dependent prostate cell growth [4]. In this view, the capability of NE to trigger the proliferation of PC-3 prostate cancer cells in α1D-AR-dependent manner has been reported [3].…”