Non-genomic actions of androgens

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.

Figure 1

Androgen actions via intracellular androgen receptor mediated pathways. Testosterone (T) can be converted to dihydrotestosterone (DHT) by the 5αR enzyme. 1) In the classical pathway, androgen freely passes through the membrane bi-layer and binds cytoplasmic androgen receptor (AR). Bound AR translocates to the nucleus, binds to a DNA response element on a promoter of an androgen responsive gene and stimulates transcription. 2) Bound AR interacts with the SH3 domain of the tyrosine kinase c-Src to activate the MAPK pathway and influence AR-mediated transcription via phosphorylation of coactivator/receptor complexes. 3) Androgen bound to steroid hormone binding globulin (SHBG) can activate SHBG receptor (SHBGR) and lead to an increase in PKA activity. PKA may influence AR-mediated transcription via alteration of phosphorylation status of AR and AR coregulators. Abbreviations: T = testosterone, DHT = dihydrotestosterone, 5αR = 5 alpha reductase enzyme, AR = androgen receptor, PKA = protein kinase A, GP = g-protein, SH2 = Src homology domain 2, SH3 = Src homology domain 3, PTK = protein tyrosine kinase, MAPK = mitogen-activated protein kinase, SHBGR = steroid hormone binding globulin receptor, cAMP = cyclic adenosine monophosphate.

Figure 2

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 GABA_A 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.