Whether through androgen membrane or membrane associated receptors/binding proteins, changes in membrane flexibility, changes in [Ca2+]i, activation of second messenger pathway or a combination of some or all of these mechanisms, the known non-genomic actions of androgens can be mediated via multiple pathways. The physiological effect of the majority of identified non-genomic stimulation in vivo remains largely unclear. In addition, non-genomic androgen effects can function independently, or in tandem, with the other genomic effects, to initiate steroid responses. The genomic and non-genomic pathways of androgen action are likely inter-linked and can act in concert to effect normal cell function.
Front Neuroendocrinol. 2008 May;29(2):169-81.
Non-genomic actions of androgens.
Foradori CD1, Weiser MJ, Handa RJ.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386261/
Abstract
Previous work in the endocrine and neuroendocrine fields has viewed the androgen receptor (AR) as a transcription factor activated by testosterone or one of its many metabolites. The bound AR acts as transcription regulatory element by binding to specific DNA response elements in target gene promoters, causing activation or repression of transcription and subsequently protein synthesis. Over the past two decades evidence at the cellular and organismal level has accumulated to implicate rapid responses to androgens, dependent or independent of the AR. Androgen's rapid time course of action; its effects in the absence or inhibition of the cellular machinery necessary for transcription/translation; and in the absence of translocation to the nucleus suggest a method of androgen action not initially dependent on genomic mechanisms (i.e. non-genomic in nature). In the present paper, the non-genomic effects of androgens are reviewed, along with a discussion of the possible role non-genomic androgen actions have on animal physiology and behavior.
Non-genomic androgen actions via changes in intracellular ion concentrations and membrane fluidity. 1) Androgen interacts with a membrane associated androgen receptor (mAR) leading to the activation of L-type calcium channels through some type of inhibitory g-protein (GP). This increase in intracellular calcium can lead to activation of PKC, and via calmodulin (CAM) activate PKA and MAPK pathways, ultimately influencing gene transcription through phosphorylation. 2) Androgen interacts with a membrane associated androgen receptor (mAR) leading to modulation of g-protein activity and subsequent activation of phospholipase C (PLC). Resulting increases in IP3 lead to the release of intracellular calcium stores from the sarcoplasmic reticulum (SR), and consequently the activation of the RAS/MEK/ERK pathway. 3) Dihydrotestosterone (DHT) metabolite 3α-Diol may interact with the GABAA receptor and lead to increases in intracellular calcium and thus membrane potential. 4) Testosterone and its metabolites can interact with phospholipids in the membrane bilayer to change membrane flexibility and subsequently alter the function of sodium/potassium ATPase and calcium ATPase. Abbreviations: T = testosterone, DHT = dihydrotestosterone, 5αR = 5 alpha reductase enzyme, AKR1C = aldo-keto reductase, 3α-Diol = 3α-androstanediol, GABA = gamma-aminobutyric acid, GP = g-protein, PKA = protein kinase A, PKC = protein kinase C, CAM = calmodulin, MAPK = mitogen-activated protein kinase, PLC = phospholipase C, IP3 = inositol 1,4,5-triphosphate, SR = sarcoplasmic reticulum, MEK = MAPK/ERK kinase, ERK = extracellular-signal regulated kinase.
Cell Mol Life Sci. 2012 May;69(10):1651-67.
Androgens and skeletal muscle: cellular and molecular action mechanisms underlying the anabolic actions.
Dubois V1, Laurent M, Boonen S, Vanderschueren D, Claessens F.
Abstract
Androgens increase both the size and strength of skeletal muscle via diverse mechanisms. The aim of this review is to discuss the different cellular targets of androgens in skeletal muscle as well as the respective androgen actions in these cells leading to changes in proliferation, myogenic differentiation, and protein metabolism. Androgens bind and activate a specific nuclear receptor which will directly affect the transcription of target genes. These genes encode muscle-specific transcription factors, enzymes, structural proteins, as well as microRNAs. In addition, anabolic action of androgens is partly established through crosstalk with other signaling molecules such as Akt, myostatin, IGF-I, and Notch. Finally, androgens may also exert non-genomic effects in muscle by increasing Ca(2+) uptake and modulating kinase activities. In conclusion, the anabolic effect of androgens on skeletal muscle is not only explained by activation of the myocyte androgen receptor but is also the combined result of many genomic and non-genomic actions.
Last edited:
