174: TMEM217–SLC9C1: Wiring the cAMP Switch for Sperm Motility and Male Fertility

️ Episode 174: TMEM217–SLC9C1: Wiring the cAMP Switch for Sperm Motility and Male Fertility

In this episode of PaperCast Base by Base, we explore a PNAS study revealing how TMEM217 forms a complex with the sperm-specific Na+/H+ exchanger SLC9C1 to organize cAMP signaling, sustain motility, and enable fertilization in mice.

Study Highlights:
Using phylogenetic profiling and interactomics, the authors identified TMEM217 as a conserved partner of the exchanger SLC9C1 and showed that both proteins localize to the principal piece of the sperm flagellum. Knockout of Tmem217 produced severe motility defects and infertility with hairpin flagellar bending, accompanied by loss of SLC9C1 and full-length soluble adenylyl cyclase, reduced cAMP levels, and dampened PKA and tyrosine phosphorylation. Co-immunoprecipitation and AlphaFold3 modeling demonstrated that TMEM217 binds the voltage-sensing domain of SLC9C1, supporting a mechanism that assembles the SLC9C1–sAC–cAMP axis during spermiogenesis. Pharmacologic boosting of cAMP paired with membrane-conditioning media restored motility and fertilization in vitro, yielding viable offspring after embryo transfer.

Conclusion:
Dissecting the TMEM217–SLC9C1 interface and local cAMP control suggests diagnostics and mutation-agnostic therapeutic strategies for asthenozoospermia and male infertility.

Reference:
Iida-Norita R, Miyata H, Ninomiya A, Emori C, Kamoshita M, Pan C, Wang H, Ikawa M. Formation of a complex between TMEM217 and the sodium-proton exchanger SLC9C1 is crucial for mouse sperm motility and male fertility. Proceedings of the National Academy of Sciences. 2025;122(42):e2513924122. https://doi.org/10.1073/pnas.2513924122

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
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Chapters

• (00:00:00) - The mystery of athenosomes
• (00:02:00) - How SLC9C1 regulates sperm motility
• (00:06:43) - Knockout SLC9C1
• (00:11:08) - TMP 217 restores sperm to full function
• (00:12:35) - Immunity of TMM217 in mammalian sperm
• (00:16:03) - Base by base science