Activation of protein kinase B/Akt by alpha1-adrenoceptors in the human prostate

Strittmatter, Frank; Walther, Sebastian; Roosen, Alexander; Rutz, Beata; Schlenker, Boris; Limmer, Sebastian; Waidelich, Raphaela; Stief, Christian G.; Gratzke, Christian; Hennenberg, Martin

doi:10.1016/j.lfs.2012.01.002

Cited by 11 publications

(13 citation statements)

References 33 publications

(63 reference statements)

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“…This may suggest possible connections between smooth muscle tone and growth in the prostate. Although such links have been proposed by various investigators, little is known about their intracellular mediators [4,8,26-28]. In cardiomyocytes, EPAC activation causes hypertrophic responses, by intervention into transcription of hypertrophic genes [13,24,25].…”

Section: Discussionmentioning

confidence: 99%

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The cAMP effector EPAC activates Elk1 transcription factor in prostate smooth muscle, and is a minor regulator of α1-adrenergic contraction

et al. 2013

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BackgroundProstate smooth muscle tone is regulated by α1-adrenoceptor-induced contraction and cAMP-mediated relaxation. EPAC is an effector of cAMP, being involved in smooth muscle relaxation and cell cycle control outside the lower urinary tract. Here, we investigated the expression and function of EPAC in human prostate tissues from patients undergoing radical prostatectomy.ResultsmRNA and protein expression of EPAC was detected in all prostate tissues by RT-PCR and Western blot analysis. Immunoreactivity was observed in stromal cells, and colocalized with immunofluorescence for α-smooth muscle actin and calponin. Under normal conditions, noradrenaline- or phenylephrine-induced contraction of prostate strips in the organ bath was not affected by the EPAC activator pCPT (SP-8-pCPT-2′-O-Me-cAMPS.NA) (30 μM). However, when the cyclooxygenase inhibitor indomethacin (50 μM) was added, EPAC activators pCPT and OME (8-CPT-2′-O-Me-cAMP.Na) (30 μM) significantly reduced contractions by low concentrations of phenylephrine. These effects were not observed on noradrenaline-induced contraction. OME and pCPT caused phosphorylation of the transcription factor Elk1 in prostate tissues. Elk1 activation was confirmed by EMSA (electrophoretic mobility shift assay), where OME and pCPT incresed Elk1 binding to a specific DNA probe.ConclusionsEPAC activation may reduce α1-adrenergic prostate contraction in the human prostate, although this effect is masked by cyclooxygenases and β-adrenoceptors. A main EPAC function in the human prostate may be the regulation of the transcription factor Elk1.

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Section: Discussionmentioning

confidence: 99%

“…Prostate growth and contraction were regarded as separate phenomenons for decades (“dynamic” and “static” component) [9]. However, it has been recently postulated that both components may be coupled to each other, although detailed mechanisms still remain an enigma [4,8,28]. …”

Section: Introductionmentioning

confidence: 99%

The cAMP effector EPAC activates Elk1 transcription factor in prostate smooth muscle, and is a minor regulator of α1-adrenergic contraction

et al. 2013

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“…Although they may be activated by motoric receptors, these pathways are frequently not involved in contraction or relaxation of smooth muscle, and may then be termed as “non‐motoric” pathways (opposed to “motoric” pathways, leading to contraction or relaxation). Intracellular signaling of prostate α 1 ‐adrenoceptors by non‐motoric pathways has been addressed by recent studies . These studies revealed detailed knowledge on intracellular signaling by α 1 ‐adrenoceptors, which might explain previous observations.…”

Section: Non‐motoric Signal Transduction By Prostate α1‐adrenoceptorsmentioning

confidence: 94%

“…protein kinase B) is a central mediator of growth and proliferation in various cell types and organs . The activation of Akt by G protein‐coupled receptors is a common, widespread principle, and has now been established for prostate α 1 ‐adrenoceptors . Akt is activated by phosphorylation at serine 473 and threonine 308, being one of them sufficient to induce Akt activation .…”

Section: Non‐motoric Signal Transduction By Prostate α1‐adrenoceptorsmentioning

confidence: 99%

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

Hennenberg

Stief

Gratzke

2013

Neurourology and Urodynamics

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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.

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“…This may be termed as “non-motoric” signaling, and comprises a panel of pathways including mitogen-activated protein kinases, Akt, and transcription factors, which are all activated by α 1 -adrenoceptors in the human prostate [Figure 2]. [23242526]…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of the lower urinary tract

2014

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Pharmacology of the lower urinary tract provides the basis for medical treatment of lower urinary tract symptoms (LUTS). Therapy of LUTS addresses obstructive symptoms (frequently explained by increased prostate smooth muscle tone and prostate enlargement) in patients with benign prostate hyperplasia (BPH) and storage symptoms in patients with overactive bladder (OAB). Targets for medical treatment include G protein-coupled receptors (α1-adrenoceptors, muscarinic acetylcholine receptors, β3-adrenoceptors) or intracellular enzymes (5α-reductase; phosphodiesterase-5, PDE5). Established therapies of obstructive symptoms aim to induce prostate smooth muscle relaxation by α1-blockers or PDE5 inhibitors, or to reduce prostate growth and volume with 5α-reductase inhibitors. Available options for treatment of OAB comprise anitmuscarinics, β3-adrenoceptor agonists, and botulinum toxin A, which improve storage symptoms by inhibition of bladder smooth muscle contraction. With the recent approval of β3-antagonists, PDE inhibitors, and silodosin for therapy of LUTS, progress from basic research of lower urinary tract pharmacology was translated into new clinical applications. Further targets are in preclinical stages of examination, including modulators of the endocannabinoid system and transient receptor potential (TRP) channels.

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Activation of protein kinase B/Akt by alpha1-adrenoceptors in the human prostate

Cited by 11 publications

References 33 publications

The cAMP effector EPAC activates Elk1 transcription factor in prostate smooth muscle, and is a minor regulator of α1-adrenergic contraction

The cAMP effector EPAC activates Elk1 transcription factor in prostate smooth muscle, and is a minor regulator of α1-adrenergic contraction

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

Pharmacology of the lower urinary tract

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