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Functional Asymmetry and Essential Structural Roles of PDE6α and PDE6β Subunits in Rod Photoreceptor Integrity

ABSTRACT: Tetrameric rod phosphodiesterase 6 (PDE6) critically regulates cyclic GMP (cGMP) levels in rod photoreceptors comprised of catalytic core α/β heterodimer and two small inhibitory γ subunits. While the rod PDE6 catalytic core is a heterodimer, the cone isoform is an α'/α' homodimer. This structural difference suggests unique roles for each rod subunit. Due to the lack of heterologous expression systems, we leveraged novel transgenic mouse models to examine the functional contributions of the N-terminal Pt motifs and the individual catalytic subunits in vivo. We generated four independent mouse lines: N-terminal deletions (PDE6αΔ2-48AA and PDE6βΔ2-46AA) and active-site mutations (PDE6αH599A and PDE6βH597A) designed to selectively abolish catalytic activity. Native mass spectrometric analysis of heterozygous mice confirmed that only wild-type enzyme was produced. While homozygous mutations in all lines caused complete photoreceptor degeneration, analysis of heterozygous lines revealed a disproportionately greater impact of PDE6β mutations on protein stability, enzymatic activity, and visual function compared to PDE6α. These findings establish that both active subunits are essential for rod integrity but uncover a significant functional asymmetry within the PDE6αβ heterodimer. Our results demonstrate that the PDE6β subunit plays a more dominant role in maintaining the structural and functional pool of the PDE6 enzyme.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Photoreceptor Cell, Retina

SUBMITTER: Fangyuan Gao

LAB HEAD: Krzysztof Palczewski

PROVIDER: PXD073183 | Pride | 2026-05-25

REPOSITORIES: Pride

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			Action	DRS
	PDE6Nterminal_DDA_inclu.raw	Raw
	PRM_AD100.raw	Raw
	PRM_AD96.raw	Raw
	PRM_AD97.raw	Raw
	PRM_AD98.raw	Raw

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