Disruption of the principal, progesterone-activated sperm Ca ²⁺ channel in a CatSper2-deficient infertile patient

Abstract

The female steroid hormone progesterone regulates ovulation and supports pregnancy, but also controls human sperm function within the female reproductive tract. Progesterone causes elevation of sperm intracellular Ca 2+ leading to sperm hyperactivation, acrosome reaction, and perhaps chemotaxis toward the egg. Although it has been suggested that progesterone-dependent Ca 2+ influx into human spermatozoa is primarily mediated by cationic channel of sperm (CatSper), the principal flagellar Ca 2+ channel of sperm, conclusive loss-of-function genetic evidence for activation of CatSper by progesterone has yet to be provided. Moreover, it is not clear whether the responsiveness of CatSper to progesterone is an innate property of human spermatozoa or is acquired as the result of exposure to the seminal plasma. Here, by recording ionic currents from spermatozoa of an infertile CatSper-deficient patient, we demonstrate that CatSper is indeed the principal Ca 2+ channel of human spermatozoa, and that it is strongly potentiated by progesterone. In addition, by recording CatSper currents from human epididymal and testicular spermatozoa, we show that CatSper sensitivity to progesterone arises early in sperm development and increases gradually to a peak when spermatozoa are ejaculated. These results unambiguously establish an important role of CatSper channel in human sperm nongenomic progesterone signaling and demonstrate that the molecular mechanism responsible for activation of CatSper by progesterone arises early in sperm development concurrently with the CatSper channel itself.CatSper ion channel | male fertility | nongenomic steroid action | sperm physiology

Flagellar ion channels of sperm: similarities and differences between species

“…Loss of any one member of the complex is detrimental to male fertility due to their interdependent protein expression in spermatozoa though CatSper␤ and CatSper␥ null mice have yet to be observed [9,19,22,24,49,74]. Humans with mutations within the CatSper1 or CatSper2 genes were also shown to be infertile revealing CatSper's importance as a general mechanism in mammalian fertility potential [6,[75][76][77][78][79][80]. By combining mouse genetics with sperm patch clamp method CatSper activity was eventually directly recorded in 2006 and CatSper was established as the principal Ca 2+ channel of mouse sperm [16].…”

“…Such observations were made in the absence of intracellular Ca 2+ , ATP, GTP, or any other soluble second messengers suggesting that the progesterone effect observed acts through a receptor directly associated with the CatSper channel and not through G-proteins or protein kinases. Further evidence for CatSper as the source of progesterone-induced Ca 2+ influx came from studies on a CatSperdeficient patient with a homozygous microdeletion in the CatSper2 gene [6,79]. These CatSper-less spermatozoa didn't produce any progesterone-activated current, and even lacked basal CatSper activity [79].…”

“…Further evidence for CatSper as the source of progesterone-induced Ca 2+ influx came from studies on a CatSperdeficient patient with a homozygous microdeletion in the CatSper2 gene [6,79]. These CatSper-less spermatozoa didn't produce any progesterone-activated current, and even lacked basal CatSper activity [79]. While the molecular identity of sperm progesterone receptor is still unknown, the binding site for a cell impermeant analog of this steroid is accessible from the extracellular space [18].…”

“…Point mutations within the CatSper1 gene as well as a deletion of the CatSper2 gene have been described in men with infertility [6,75,77,79]. Loss of expression of the CatSper2 gene results in disruption of the entire complex as no appreciable CatSper current is observed in patient spermatozoa as well as a complete lack of detection of other CatSper complex members at the protein level [79].…”

“…Point mutations within the CatSper1 gene as well as a deletion of the CatSper2 gene have been described in men with infertility [6,75,77,79]. Loss of expression of the CatSper2 gene results in disruption of the entire complex as no appreciable CatSper current is observed in patient spermatozoa as well as a complete lack of detection of other CatSper complex members at the protein level [79]. Antibody recognition of CatSper is restricted to the principle piece of the sperm flagella and recent work by Chung et al suggest that CatSper is localized to linearly arranged Ca 2+ signaling domains along the length of the cellular structure [74].…”