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Norepinephrine (NE) transporters (NETs) terminate noradrenergic synaptic transmission and represent a major therapeutic target for antidepressant medications. NETs and related transporters are under intrinsic regulation by receptor and kinase-linked pathways, and clarification of these pathways may suggest candidates for the development of novel therapeutic approaches. Syntaxin 1A, a presynaptic soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, interacts with NET and modulates NET intrinsic activity. NETs colocalize with and bind to syntaxin 1A in both native preparations and heterologous systems. Protein kinase C activation disrupts surface NET/syntaxin 1A interactions and downregulates NET activity in a syntaxin-dependent manner. Syntaxin 1A binds the NH(2) terminal domain of NET, and a deletion of this domain both eliminates NET/syntaxin 1A associations and prevents phorbol ester-triggered NET downregulation. Whereas syntaxin 1A supports the surface trafficking of NET proteins, its direct interaction with NET limits transporter catalytic function. These two contradictory roles of syntaxin 1A on NET appear to be linked and reveal a dynamic cycle of interactions that allow for the coordinated control between NE release and reuptake.
Prostaglandins, lipoid substances discovered in human semen as modulators of uterine muscle contractility, are known to play significant roles in virtually all mammalian organ systems, but their male reproductive functions are unclear. Cyclooxygenase, the rate-limiting enzyme in prostaglandin synthesis, occurs in two isoforms distinguished on the basis of constitutive (COX-1) or inducible (COX-2) expression patterns in mammalian tissues. However, in the adult rat male reproductive system, immunohistochemistry and Western and Northern analysis showed that COX-2 is the predominant isoform and is heavily localized to the epithelium of the distal vas deferens, where constitutive expression is manyfold greater than in any other organs of the body. COX-2 is not detected in the proximal one-half of the vas nor in the testis, epididymis, seminal vesicles, or prostate. Elimination of luminal sperm by vasectomy does not affect COX-2 levels, whereas castration severely depletes COX-2 and androgen replacement after castration restores COX-2, indicating that COX-2 expression in the vas is androgen dependent. Because the distal vas also comprises an extensive submucosal venous plexus connected to the penile corpora cavernosa, prostaglandins from the vas may play a role in erection.
Antibodies to rabbit acrosome stabilizing factor (ASF) were raised in mice and proved monospecific on Western electroblots . Anti-ASF was utilized to immunolabel tissue sections of male reproductive tract organs. Staining of principal cell cytoplasm was observed primarily in the corpus epididymidis (Regions 6 and 7), and secondarily in the cytoplasm of principal cells of the distal cauda epididymidis (Region 8b ) and the columnar cells of the vas deferens epithelium. The microvilli of principal cells in the proximal cauda epididymidis (Region 8a ) were densely stained. Spermatozoa appeared uniformly stained within the lumen of the corpus epididymidis and staining intensity increased distally. The Golgi region of corpus principal cells was not stained, nor were other cell types in this region. Testis, caput epididymidis, and accessory sex organs were not stained. Synthesis of ASF by corpus epididymidis was shown by immunoprecipitation of radiolabeled ASF from organ cultures of specific epididymal segments. Scant amounts of synthesis were also detected in the cauda epididymidis and vas deferens. The large subunit of ASF, immunoprecipitated from the corpus epididymidis, is 2000-4000 daltons larger than the large subunit of ASF from more distal regions of the reproductive tract, suggesting modification of this component.
A cDNA representing a 5.2-kb defective, endogenous murine leukemia proviral sequence (EPI-EPS) was isolated from a C57BL/6 mouse cDNA epididymal library. Northern blot analysis demonstrated that EPI-EPS was predominantly expressed in the C57BL/6 mouse epididymis and vas deferens with 10-fold lower expression in the seminal vesicle, kidney, and submandibular gland. Analysis of tissues from other inbred strains of mice as well as the wild mouse, Mus musculus musculus, showed a similar pattern of tissue expression. EPI-EPS expression was also highly androgen regulated in both the reproductive and nonreproductive tissues of the C57BL/6 strain. However, a differential response to testosterone replacement was observed between tissues. Expression of EPI-EPS mRNA in the epididymis and vas deferens exhibited only a partial recovery to precastration levels after testosterone replacement; in the kidney and submandibular gland there was a complete recovery of EPI-EPS expression. Finally, EPI-EPS expression was also highly restricted in the female tissues, with expression limited to the oviduct and uterus. EPI-EPS, however, was not estrogen regulated in the female. These results suggest that a proviral sequence, EPI-EPS, is expressed in M. m. musculus and several inbred strains of mice due to its integration near a highly tissue-specific and androgen-regulated genetic locus.