Mechanisms of Hyperactivation

Molecular Mechanisms of Sperm Hyperactivation

Calcium (Ca²⁺)

Ca²⁺ plays a major role in regulating hyperactivated motility. Extracellular Ca²⁺ is required to maintain hyperactivation in various animal models including hamsters and mouse. In comparison to activated sperm, hyperactivated sperm have a higher cytoplasmic Ca²⁺ concentrations within the flagella than activated sperm.  

The crucial site for the action of Ca²⁺ is the axoneme. The mechanism by which Ca²⁺ reaches the axoneme in  the flagellum to switch on hyperactivation in sperm is still unknown. There may be an intracellular Ca²⁺  store in the sperm flagellum providing the increase in intracellular Ca²⁺ to the axoneme.Inositol 1,4,5-trisphosphate (IP3) releases Ca²⁺from some stores, and IP3 receptors have been found on the base of the flagellum. 

cAMP

Increased intracellular cAMP has been associated with sperm hyperactivated motility. Various researchers have suggested that cAMP might be involved in the regulation of flagellar 'whip like' mortion by maintaining intracellular Ca²⁺ at correct concentration. Ca²⁺ and cAMP may also modulate protein phosphorylation. Increased  phosphorylation of tyrosine  in the flagella is associated with hyperactivated motility in various specious including hamsters and monkeys.  For example, tyrosine phosphorylation been associated with heat-induced hyperactivation in human sperm.

 Although cAMP and Ca²⁺ + regulate hyperactivated motility through different pathways, they also modulate the actions of each other. Ca²⁺ causes significant increases in cAMP and activates the Mg2+-dependent adenylyl cyclase of guinea-pig sperm.

In summary, from the available information, it appears that Ca²⁺ is the most important factor regulating hyperactivation, and that cAMP is required but is not sufficient for expression of hyperactivation. The diagram below summarizes the proposed mechanisms of sperm hyperactivation.

sSignal stimulation results in activation pathways leading to increases in Ca²⁺ and cAMP . Unknown physiological signals activate phospholipase C (PLC) through a heterotrimeric G protein (Gq/11)-coupled receptor (R1) and produce IP3. Binding of IP3 to IP3 receptors (IP3R) on intracellular Ca²⁺ stores causes an increase in cytoplasmic Ca²⁺. Activation of adenylyl cyclase (AC) through high cytoplasmic Ca²⁺ and possibly G proteins (G?) and membrane potential increases intracellular cAMP.  The increased cAMP can bind to cyclic nucleotide-gated channels (CNG) to induce Ca²⁺ influx. Increased cAMP activates protein kinase A (PKA). PKA  phosphorylates axonenal or fibrous sheath proteins. This results in increased flagellar beating (hyperactivation). High cytoplasmic Ca²⁺ and Ca²⁺/calmodulin complex are responsible for asymmetrical bending of flagella. This is associated with hyperactivation.

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