**6.2 Role of calcium in motility**

Calcium plays a key role in sperm function by different aspects. Recent studies have been demonstrated that in knockout mice there are at least four components participate in the intracellular regulation of calcium level and initiation of sperm motility. These are CatSper1, CatSper2, Cav2.3 and PMCA4. CatSper1 are localized in the principle piece of sperm and it is a voltage gated Ca2+ channels of the testis. Lacking or any mutation in CatSper1 gene reduces the progressive motility and causes infertility. A sperm cell that lacks the CatSper1 showed progressive motility but failed to develop hyperactivated motility [25]. CatSper2 present in flagellum shows similarity to CatSper1 and it is also a voltage-gated ion channel. Sperm of mice having knockout CatSper2 gene depict decreased flagellar amplitude and also failed to develop hyperactivated motility [26]. Disruption of gene for PMCA4, that have Ca2+/calmodulin dependent ATPase activity involve in efflux of Ca2+, also causes infertility in men. In developing sperm cells and sperm flagellum the cyclic nucleotide gated Ca2+ channels are present. The role of these channels is to regulate the influx of calcium in various micro domains of the flagella [26].

### **6.3 cAMP and motility**

During sperm motility regulation, cAMP is the second key messenger. Adenylate cyclase converts the ATP into cAMP. Thus, the level of cAMP increases and in turn activates the cAMP dependent kinase A (PKA) which phosphorylates the serine and threonine residues in the flagellum, which ultimately causes the phosphorylation of tyrosine residues in the proteins [27, 28]. In most cells the adenylyl cyclase is activated by G protein in response to external stimuli. In mouse sperm the plasma membrane bounds (mACs) activated by G protein take a part in the acrosome reaction, and in chemotaxis and hyperactivation in human sperm [29]. It was

**31**

*Insights of Sperm Pathology and Its Association with Infertility*

sperm motility. The activity of soluble adenylyl cyclase is augmented by HCO3

increased activation of enzymes (adenylyl cyclase) and by reducing the substrate inhibition that happens at higher concentration of ATP-Mg2+. Due to low level of

<sup>−</sup>, activity of soluble adenylyl cyclase would be reduced in sperm by substrate

PKA causes the phosphorylation of tyrosine residue of flagellar proteins. The proteins anchoring with PKA site (AKAP3, AKAP4 and TAKAP-80) in the fibrous sheath, point out that the main role of this structure is to bind PKA in the principle piece of flagellum [31]. Regulatory and catalytic subunits are present in PKA holoenzyme. Four genes (RIα, RIβ, RIIα and RIIβ) are present in regulatory subunits (R subunit) in human and mouse; three catalytic (C subunit) Cα, Cβ and Cγ in human, and two C subunit Cα and Cβ in mice. The cAMP binding site are present in R and C subunits. C subunits is released when cAMP binds to R subunits and their catalytic site is activated by cAMP. The R and C subunits are involved in the motility of sperm (**Figure 3**).

Oxidative stress is a state which causes disproportion between systemic reactive oxygen species and detoxifying capability of biological system to neutralize the reactive intermediates, also called antioxidant defenses. Spermatozoa have antioxidant defense mechanism that quench the ROS and therefore protects the cells of gonads and mature spermatozoa from oxidative damage [32]. Statistics from United States depicted that the major cause of male infertility is ROS. In 30–40% of infertile men's seminal plasma, there is an increase in the level of ROS [33]. In

1.At the level of sperm plasma membrane—by nicotinamide adenine dinucleo-

2.At the level of mitochondria—by nicotinamide adenine dinucleotide-

The production of ROS at the level of mitochondria is the chief source. Large concentration of mitochondria is present in spermatozoa because of a constant need of energy to spermatozoa for motility. In semen, presence of nonfunctional spermatozoa considerably increases the level of ROS that in turn impair the function of mitochondria and motility of sperm. In human spermatozoa, ROS which is produced

in the presence of iron and copper. OH<sup>−</sup> affects the function of sperm by disrupting the fluidity of membrane [35, 36]. Recent studies depicting that O2 production in spermatozoa showed the presence of calcium dependent NADPH oxidase also called NOX5 has been residing in acrosomal and midpiece region of spermatozoa [37]. Initially the NOX5 resides in human testis. It is activated upon binding of calcium to its cytosolic domain and causes conformational changes in cells [35]. ROS is generated during the normal metabolism of cells. Under physiological conditions the mitochondrial respiration is the chief source of superoxide anion radicals. Quality of sperm and

function is affected by the high concentration of ROS and is potentially toxic.

<sup>−</sup>. It reacts with itself to generate H2O2 by dismutation.

<sup>−</sup> generates most destructive and reactive OH<sup>−</sup> by Haber-Weiss reaction

**7. Effect of oxidative stress on male reproductive system**

spermatozoa ROS are generated by two methods.

dependent oxidoreductase reaction [34].

tide phosphate oxidase system.

in large concentration is O2

H2O2 and O2

<sup>−</sup> and Ca2+ are inculpated in cAMP regulated activation of

<sup>−</sup> with

*DOI: http://dx.doi.org/10.5772/intechopen.90950*

inhibition stored in epididymis [30].

demonstrated that HCO3

**6.4 PKA and motility**

HCO3

demonstrated that HCO3 <sup>−</sup> and Ca2+ are inculpated in cAMP regulated activation of sperm motility. The activity of soluble adenylyl cyclase is augmented by HCO3 <sup>−</sup> with increased activation of enzymes (adenylyl cyclase) and by reducing the substrate inhibition that happens at higher concentration of ATP-Mg2+. Due to low level of HCO3 <sup>−</sup>, activity of soluble adenylyl cyclase would be reduced in sperm by substrate inhibition stored in epididymis [30].
