Adrenal gland in mammalsInmammals, theadrenal glands(also known assuprarenal glands) areendocrine glandsthat sit at the top of thekidneys; in humans, the right adrenal gland is triangular shaped, while the left adrenal gland is semilunar shaped.[1]They are chiefly responsible for releasinghormonesin response tostressthrough thesynthesisofcorticosteroidssuch ascortisolandcatecholaminessuch asadrenaline(epinephrine) andnoradrenaline. These endocrine glands also produceandrogensin their innermost cortical layer. The adrenal glands affect kidney function through the secretion ofaldosterone, and recent data (1998) suggest that adrenocortical cells underpathologicalas well as underphysiologicalconditions showneuroendocrineproperties; within the normal adrenal, this neuroendocrine differentiation seems to be restricted to cells of thezona glomerulosaand might be important for anautocrineregulation of adrenocortical function.[2]Structure[edit]The adrenal glands are located in theretroperitoneumsuperior to thekidneys, they are quadrilaterial in shape and are situated bilaterally. The combined weight of the adrenal glands in an adult human ranges from 7 to 10grams.[3]They are surrounded by anadipose capsuleandrenal fascia.Each adrenal gland has two distinct structures, the outeradrenal cortexand the innermedulla, both of which produce hormones. The cortex mainly producescortisol,aldosteroneandandrogens, while the medulla chiefly producesadrenalineandnoradrenaline. In contrast to the direct innervation of the medulla, the cortex is regulated byneuroendocrinehormones secreted from thepituitary glandwhich are under the control of thehypothalamus, as well as by therenin-angiotensin system.Cortex[edit]Main article:Adrenal cortexTheadrenal cortexis devoted to production ofcorticosteroidandandrogenhormones. Specific cortical cells produce particular hormones includingaldosterone,cortisol, andandrogenssuch asandrostenedione. Under normal unstressed conditions, the human adrenal glands produce the equivalent of 3540mg of cortisone acetate per day.[4]The adrenal cortex comprises three zones, or layers. Thisanatomic zonationcan be appreciated at the microscopic level, where each zone can be recognized and distinguished from one another based on structural and anatomic characteristics.[5]The adrenal cortex exhibitsfunctional zonationas well: by virtue of the characteristic enzymes present in each zone, the zones produce and secrete distinct hormones.[5]Zona glomerulosa[edit]The outermost layer, thezona glomerulosais the main site for production ofaldosterone, amineralocorticoid, by the action of the enzymealdosterone synthase(also known asCYP11B2).[6][7]Aldosterone is largely responsible for the long-termregulation of blood pressure.[8]The expression of neuron-specific proteins in the zona glomerulosa cells of human adrenocortical tissues has been predicted and reported by several authors[2][9][10]and it was suggested that the expression of proteins like theneuronal cell adhesion molecule(NCAM) in the cells of the zona glomerulosa reflects the regenerative feature of these cells, which would lose NCAM immunoreactivity after moving to thezona fasciculata.[2][11]However, together with other data on neuroendocrine properties of zona glomerulosa cells, NCAM expression may reflect a neuroendocrine differentiation of these cells.[2]

Paraffin sections ofhuman adrenalsimmunostained forneuronal cell adhesion molecule(NCAM). Immunohistochemistry was carried out using 4-amino-9-ethylcarbazole(AEC; Dinanova, Hamburg, Germnay) and were counterstained with hematoxylin. Staining for NCAM was restricted to thezona glomerulosa(zg) and the adrenal medulla (m); a: x 20; b: x 200.[2].Zona fasciculata[edit]Situated between the glomerulosa and reticularis, thezona fasciculatais responsible for producingglucocorticoids, such as11-deoxycorticosterone,corticosterone, andcortisolin humans.[12]Zona reticularis[edit]The inner most cortical layer, thezona reticularisproducesandrogens, mainlydehydroepiandrosterone(DHEA),DHEA sulfate(DHEA-S), andandrostenedione(the precursor totestosterone) in humans.[12]Medulla[edit]Theadrenal medullais the core of the adrenal gland, and is surrounded by the adrenal cortex. It secretes approximately 20% noradrenaline (norepinephrine) and 80% adrenaline (epinephrine).[12]Thechromaffin cellsof the medulla, named for their characteristic brown staining withchromic acidsalts, are the body's main source of the circulatingcatecholaminesadrenaline and noradrenaline. Catecholamines are derived from the amino acidtyrosineand these water-soluble hormones are the major hormones underlying thefight-or-flight response.To carry out its part of this response, the adrenal medulla receives input from thesympathetic nervous systemthroughpreganglionic fibersoriginating in thethoracic spinal cordfrom T5T11.[13]Because it is innervated bypreganglionic nerve fibers, the adrenal medulla can be considered as a specializedsympathetic ganglion.[13]Unlike other sympathetic ganglia, however, the adrenal medulla lacks distinct synapses and releases its secretions directly into the blood.Cortisol also promotes adrenaline synthesis in the medulla. Produced in the cortex, cortisol reaches the adrenal medulla and at high levels, the hormone can promote the upregulation ofphenylethanolamineN-methyltransferase(PNMT), thereby increasing adrenaline synthesis and secretion.[5]

Blood supply[edit]Although variations of the blood supply to the adrenal glands (and indeed the kidneys themselves) are common, there are usually three arteries that supply each adrenal gland: Thesuperior suprarenal arteryis provided by theinferior phrenic artery Themiddle suprarenal arteryis provided by theabdominal aorta Theinferior suprarenal arteryis provided by therenal arteryVenousdrainage of the adrenal glands is achieved via thesuprarenal veins: Theright suprarenal veindrains into theinferior vena cava Theleft suprarenal veindrains into the leftrenal veinor the leftinferior phrenic vein.Thesuprarenal veinsmay formanastomoseswith theinferior phrenic veins. Since the right supra-renal vein is short and drains directly into the inferior vena cava it is likely to injure the latter during removal of right adrenal for various reasons.The adrenal glands and thethyroid glandare the organs that have the greatest blood supply per gram of tissue. Up to 60arteriolesmay enter each adrenal gland.[14]This may be one of the reasons lung cancer commonly metastasizes to the adrenals.Function[edit]Aldosterone and mineralocorticoids[edit]Aldosterone's effects are on thedistal convoluted tubuleandcollecting duct of the kidneywhere it causes increased reabsorption of sodium and increased excretion of both potassium (by principal cells) and hydrogen ions (by intercalated cells of the collecting duct).[8]Sodium retention is also a response of the distal colon, and sweat glands to aldosterone receptor stimulation. Although sustained production of aldosterone requires persistentcalciumentry through low-voltage activatedCa2+channels, isolated zona glomerulosa cells are considered nonexcitable, with recorded membrane voltages that are too hyperpolarized to permitCa2+channels entry.[15]However, mouse zona glomerulosa cells within adrenal slices spontaneously generate membrane potential oscillations of low periodicity; this innate electrical excitability of zona glomerulosa cells provides a platform for the production of a recurrent Ca2+channels signal that can be controlled byangiotensin IIand extracellularpotassium, the 2 major regulators of aldosterone production.[15]Angiotensin II originates from plasmaticangiotensin Iafter the conversion ofangiotensinogenbyreninproduced by thejuxtaglomerular cellsof thekidney.[12]Cortisol and glucocorticoids[edit]Cortisol is the main glucocorticoid under normal conditions and its actions include mobilization of fats, proteins, and carbohydrates, but it does not increase under starvation conditions.[12]Additionally, cortisol enhances the activity of other hormones including glucagon and catecholamines. The zona fasciculata secretes a basal level of cortisol but can also produce bursts of the hormone in response toadrenocorticotropic hormone(ACTH) from theanterior pituitary.Androgen production[edit]Adrenaline and noradrenaline[edit]Clinical significance[edit] Severaladrenal tumorscause symptoms because they result in the over- or underproduction of certain hormones by the adrenal gland. Inhyperaldosteronismthe adrenal glands produce too much aldosterone. Inpheochromocytomathe adrenal glands secretes excessive amounts of catecholamines. In endogenousCushing's syndromethe adrenal glands produce too much cortisol. Adrenal insufficiencydenotes a group of diseases characterized by underproduction of cortisol or aldosterone. They can be caused by problems in the adrenal glands themselves, or by impairment of the pituitary gland or hypothalamus. TheACTH stimulation testmay assist in diagnosis. Addison's diseaseis a rare disorder in which the adrenal glands do not produce sufficient amounts ofglucocorticoids(mainly cortisol). This can be caused by anautoimmune reaction, by certain infections or by some other rarer causes. Congenital adrenal hyperplasiasare genetic defects of enzymes involved in cortisol production and can affect sex characteristics of affected patients. WaterhouseFriderichsen syndromeis adrenal gland failure due to bleeding into the adrenal glands, caused by severe bacterial infection. Isolatedhypoaldosteronismcan rarely occur due toaldosterone synthasedeficiency Absent adrenal gland, rare congenital condition

Nuclear binding and degradationWhen the RNA polymerase reaches the end of mRNA coding genes, the nascent transcript is cleaved and a poly(A) tail is appended to the 3 end of the molecule. A large complex of proteins, the cleavageand polyadenylation machinery, is responsible for the recognition of 3-processing signals and for cleavage, and an associated poly(A) polymerase (Pap1p) synthesizes the terminal polyadenylate (Buratowski, 2005andZhao etal., 1999). The presence of a 3 poly(A) tail is both a signal that the mRNA synthesis is complete and a functional element that will promote export from the nucleus and translation. Its position close to the end of the coding region of the mRNA is also a hallmark of quality, preventing degradation by the quality control system that detects the occurrence of premature stop codons. The size of the poly(A) tail (70100 nt inSaccharomyces cerevisiae) is also crucial, as its shortening in the cytoplasm is the first event committing the transcript to degradation. Poly(A)-binding proteins are required for a readout of the tail functions and to influence its synthesis and length by affecting the processivity of the poly(A) polymerase (Mangus etal., 2003). InS. cerevisiae, two proteins (Pab1p and Nab2p) that recognize the poly(A) tail have been described and extensively studied. Although both proteins shuttle between the nucleus and the cytoplasm, their main subcellular localization is cytoplasmic (Pab1p) and nuclear (Nab2p). While a cytoplasmic role for Pab1p in translation is clearly established, the nuclear role of the two proteins is still a matter of controversy, and it is not clear which one is directly involved in the regulation of poly(A) tail synthesis and its nuclear function(s) (Dunn etal., 2005andHector etal., 2002).Poly(A) tailing is not only instrumental toexpress the message carried by an RNA, but also to promote maturation or degradation. A different polyadenylation pathway, dependent on an alternative poly(A) polymerase (Trf4p or Trf5p inS.cerevisiae), exists (Houseley and Tollervey, 2008). This pathway tags a different class of substrates for faster (or more efficient) degradation by the nuclear exosome, a protein complex endowed with both exo- and endonuclease activity (Lebreton and Seraphin, 2008). In many cases, degradation is halted by stable ribonucleoprotein complexes, and exonuclease trimming results in the production of mature and stable RNAs, as in the case of the small nucleolar RNAs (snoRNAs). It is unclear whether degradative polyadenylation is coupled to the termination of transcription and/or to 3 end processing of the primary transcript or if it occurs posttranscriptionally on substrates that cannot be degraded efficiently by the exosome, for instance due to secondary structures. Importantly, it is also unclear whether the unstructured poly(A) tail is required invivo to promote more efficient degradation or whether it somehow serves for addressing the exosome to the substrate.Thus, the poly(A) tail can promote very different fates, which raises the important question of what differs in the readout of the same signal. One possibility is that binding of a poly(A)-binding protein (e.g., Pab1p) after cleavage and polyadenylation marks the poly(A) tails that have a cytoplasmic fate while masking at the same time a dangerous degradation signal. A poly(A) tail that would not associate with poly(A)-binding proteins during or shortly after synthesis (as could be the case of a tail added posttranscriptionally by Trf4p) would be exposed to the degradative activity of the exosome. The paper from Bachand and colleagues in this issue ofMolecular Cell(Lemay etal., 2010) challenges to some extent this view and provides a unique perspective on the function of poly(A)-binding proteins. The authors show that deletion of the gene encoding a nuclear poly(A)-binding protein inSchizosaccharomyces pombe, Pab2, leads to stabilization of extended forms of several snoRNAs. Importantly, these precursors to the mature snoRNAs are polyadenylated by a poly(A) polymerase that turns out to be distinct from theS. pombehomolog of Trf4p. The same extended forms are stabilized by deletion of Rrp6p (a nuclear exonuclease that is associated with the exosome), but in a double mutantrrp6pab2 a further stabilization of the precursors was not observed, suggesting that Rrp6p and Pab2p work in the same pathway. Importantly, Pab2p binds these polyadenylated forms invivo and interacts directly with Rrp6p, both invivo and invitro. This suggests that the binding of Pab2 to the poly(A) tail is required to target these extended transcripts to degradation via the direct interaction between Pab2p and the exosome (Figure1). These findings have two important implications: first, they provide evidence that the presence of the poly(A) tail can recruit the exosome (as opposed to favoring its catalytic activity); second, the mere (and presumably early) binding of a poly(A)-binding protein is not sufficient to prevent degradation but actually, in some conditions, promotes it. The authors suggest that this might reveal the existence of an alternative pathway to generate a mature form of snoRNAs: either transcription ends at a proximal site (presumably via the action of a homolog of theS. cerevisiaeNrd1 complex, involved in termination of independently transcribed snoRNA genes) or it ends at a downstream site where the nascent transcript is processed by the cleavage and polyadenylation machinery and where it interacts with Pab2b. The presence of Pab2 would lead to the recruitment of the exosome and subsequent trimming of these transcripts to their mature length.

However, there is more to the story. In another recent article (Lemieux and Bachand, 2009), the same group shows that Pab2p also binds cotranscriptionally to mRNAs and that this occurs even before the poly(A) tail synthesis (Figure1B). In spite of this, no stabilization of the tested mRNAs nor an effect on the length of the poly(A) tail was observed inpab2 cells (Lemay etal., 2010), suggesting that the presence of Pab2p on the poly(A) tail does not target these transcripts to the nuclear degradation machinery. Rather, Pab2p is found in polysomes, indicating that it remains associated with the mRNA during translation. Therefore, what determines whether RNAs that share the same tail, possibly generated by the same apparatus and with the same protein bound to it, are targeted to the exosome for degradation or to the cytoplasm for translation remains a hot question. It is obviously possible that other proteins, aside from Pab2p, bind differentially to mRNAs and snoRNAs, but it remains unexplained how these species are distinguished in the act of transcription if they are processed by the same 3 end apparatus. One possibility is that their fate is determined kinetically via a take the money and run strategy. If the RNA is not exported fast enough from the nucleus, it is targeted to a default exosome pathway for degradation or processing. If so, the presence of Pab2p on the poly(A) tail might not have a function in the nucleus other than that of a trigger that would determine the threshold above which the nuclear residency time is not compatible with the life of an mRNA.