Hyperactivated sperm motility driven by CatSper2 is required for fertilization

Abstract

Elevations of sperm Ca 2؉ seem to be responsible for an asymmetric form of motility called hyperactivation, which is first seen near the time of fertilization. The mechanism by which intracellular Ca 2؉ concentrations increase remains unknown despite considerable investigation. Although several prototypical voltage-gated calcium channels are present in spermatozoa, they are not essential for motility. Furthermore, the forward velocity and percentage of motility of spermatozoa are associated with infertility, but their importance relative to hyperactivation also remains unknown. We show here that disruption of the gene for a recently described sperm-specific voltage-gated cation channel, CatSper2, fails to significantly alter sperm production, protein tyrosine phosphorylation that is associated with capacitation, induction of the acrosome reaction, forward velocity, or percentage of motility, yet CatSper2 ؊͞؊ males are completely infertile. The defect that we identify in the null sperm cells is a failure to acquire hyperactivated motility, which seems to render spermatozoa incapable of generating the ''power'' needed for penetration of the extracellular matrix of the egg. A loss of power is suggested also by experiments in which the viscosity of the medium was increased after incubation of spermatozoa in normal capacitating conditions. In highviscosity medium, CatSper2-null spermatozoa lost the ability to swim forward, whereas wild-type cells continued to move forward. Thus, CatSper2 is responsible for driving hyperactivated motility, and, even with typical sperm forward velocities, fertilization is not possible in the absence of this highly active form of motility.hyperactivation ͉ spermatozoa ͉ infertility

Male Mice That Do Not Express Group VIA Phospholipase A2 Produce Spermatozoa with Impaired Motility and Have Greatly Reduced Fertility

“…The iPLA 2 ␤-null mouse thus joins a group of recently reported mouse models involving gene disruption that produce selective impairment of male (but not female) fertility associated with reduced motility of spermatozoa. Other such models include disruption of the genes for soluble adenylyl cyclase (20), for the voltage-gated cation channels Catsper1 and CatSper2 (27)(28)(29), and for plasma membrane Ca 2ϩ -ATPase 4 (25).…”

“…Signals that regulate motility of spermatozoa include changes in cAMP and intracellular [Ca 2ϩ ] (27)(28)(29)(30)(31)(32)(33), and both parameters are affected by products of PLA 2 action, which include a free fatty acid and a 2-lysophospholipid. Mice deficient in soluble adenylyl cyclase activity are infertile because of a severe sperm motility defect (20), and both abnormalities also occur in mice null for the catalytic subunit of cAMP-dependent protein kinase A (33).…”

Flagellar ion channels of sperm: similarities and differences between species

“…This weak voltage dependency is thought to be the result of heterogeneity of the arginine and lysine composition of the putative voltage sensor domains within the CatSper ␣ subunits. The characteristic CatSper current (I CatSper ) is lost in mice lacking any of the CatSper ␣ subunits (CatSper1-4) or the accessory subunit CatSper ␦ and, as previously mentioned, are all infertile due to an inability of CatSper null spermatozoa to hyperactivate resulting in an inability of sperm to pass into the oviduct to reach the egg [9,10,16,21,22,24,[71][72][73][81][82][83].…”

Phosphorylation of Sperm Axoneme Central Apparatus Protein SPAG16L by a Testis-specific Kinase, TSSK-2.

“…During fertilization, spermatozoa undergo a series of changes before and during egg binding that are related to acquisition of the ability to fuse with the oocyte, including major changes in the phosphorylation of spermatozoa proteins. Increased protein phosphorylation is associated with capacitation, hyperactivated motility, zona pellucida binding, acrosome reaction and sperm-oocyte binding and fusion [33][34][35][36][37]. Several flagellar proteins are known to be phosphorylated during capacitation including the fibrous sheath proteins CABYR and AKAP 3 & 4 [38][39][40][41].…”