Nitric Oxide and Cyclic Nucleotides: Their Roles in Junction Dynamics and Spermatogenesis

Abstract

Spermatogenesis is a highly complicated process in which functional spermatozoa (haploid, 1n) are generated from primitive mitotic spermatogonia (diploid, 2n). This process involves the differentiation and transformation of several types of germ cells as spermatocytes and spermatids undergo meiosis and differentiation. Due to its sophistication and complexity, testis possesses intrinsic mechanisms to modulate and regulate different stages of germ cell development under the intimate and indirect cooperation with Sertoli and Leydig cells, respectively. Furthermore, developing germ cells must translocate from the basal to the apical (adluminal) compartment of the seminiferous epithelium. Thus, extensive junction restructuring must occur to assist germ cell movement. Within the seminiferous tubules, three principal types of junctions are found namely anchoring junctions, tight junctions, and gap junctions. Other less studied junctions are desmosome-like junctions and hemidesmosome junctions. With these varieties of junction types, testes are using different regulators to monitor junction turnover. Among the uncountable junction modulators, nitric oxide (NO) is a prominent candidate due to its versatility and extensive downstream network. NO is synthesized by nitric oxide synthase (NOS). Three traditional NOS, specified as endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS), and one testis-specific nNOS (TnNOS) are found in the testis. For these, eNOS and iNOS were recently shown to have putative junction regulation properties. More important, these two NOSs likely rely on the downstream soluble guanylyl cyclase/cGMP/protein kinase G signaling pathway to regulate the structural components at the tight junctions and adherens junctions in the testes. Apart from the involvement in junction regulation, NOS/NO also participates in controlling the levels of cytokines and hormones in the testes. On the other hand, NO is playing a unique role in modulating germ cell viability and development, and indirectly acting on some aspects of male infertility and testicular pathological conditions. Thus, NOS/NO bears an irreplaceable role in maintaining the homeostasis of the microenvironment in the seminiferous epithelium via its different downstream signaling pathways.

Up regulation of nitric oxide synthase–nitric oxide system in the testis of rats undergoing autoimmune orchitis

“…At sustained NO levels lower than 1 M NO actions are direct, for instance, NO can activate guanylate cyclase (GC) and MAP kinase signalling pathways. It is above 1 M NO that nitrosation of critical proteins such as poly ADP ribose polymerase and caspases involved in apoptosis occurs (Lee and Cheng 2008;Thomas et al 2008). In consonance with these concepts, a potential role for NO in the control of testicular function in health and disease is suggested.…”

“…Moreover, Lee and Cheng (2008) demonstrated that NOS/sGC/protein kinase G (PKG) participates in the regulation of the blood testis barrier.…”

Disturbed Relaxin Signaling Pathway and Testicular Dysfunction in Mouse Offspring upon Maternal Exposure to Simazine

“…Both pathways are activated upon relaxin binding to Rxfp1, leading to the stimulated production of NO. Three major isoforms of Nos enzymes exist: endothelial Nos (Nos3) and neuronal Nos (Nos1), which are responsible for the continuous basal release of NO, and inducible Nos (Nos2), which is considered to be the more critical isoform, as its expression can be controlled by external factors [22]. NO is a small, diffusible, short-lived free radical gas active in diverse biological responses.…”

Role of reactive nitrogen species in male infertility

“…Each isoform has a reductase domain that contains a compound known as tetrahydrobiopterin (BH4), which is essential for efficient production of NO [24,25]. Interestingly, a testis-specific subclass of nNOS, known as TnNOS, has been recently identified as a major contributor to the formation of NO [31-34]. TnNOS is found to localize solely in the Leydig cells of the testis, thereby suggesting its involvement in steroidogenesis.…”