# Protein inhibitor of retinal membrane guanylyl cyclase suppresses cGMP synthesis in photoreceptors

## TL;DR

A new protein inhibitor reduces harmful cGMP synthesis in photoreceptors, potentially preventing inherited blindness.

## Contribution

The first specific protein inhibitor of retinal guanylyl cyclase (PIGCY) was developed and tested in photoreceptors.

## Key findings

- PIGCY reduces RetGC activity in mouse retinas and isolated rod outer segments.
- PIGCY accumulates in photoreceptor outer segments and inhibits GCAP-stimulated RetGC activity.
- PIGCY modifies GCAP1 to suppress RetGC function without activating it.

## Abstract

Retinal membrane guanylyl cyclase (RetGC) regulated by RetGC activating proteins (GCAPs) imparts light sensitivity to rods and cones by producing cyclic GMP (cGMP) to open cGMP-gated channels in the photoreceptor outer segments. However, excessive cGMP synthesis by deregulated RetGC:GCAP complex provokes cone-rod degeneration and causes congenital blindness. We developed the first to date specific protein inhibitor of retinal guanylyl cyclase (PIGCY) capable of reducing RetGC activity in photoreceptor outer segment. PIGCY was constructed by modifying GCAP1 to eliminate its ability to activate RetGC while increasing its affinity for RetGC. PIGCY uncouples RetGC1:GCAP1 complex in vitro, reducing Vmax and increasing KmGTP of RetGC activity. PIGCY inhibits both basal and GCAP-stimulated RetGC activity from wildtype, GCAP1−/−, GCAP2−/−, and GCAPs−/− mouse retinas homogenates and in isolated rod outer segments. When expressed in mouse rods, PIGCY accumulates in outer segments and decelerates endogenous GCAP-stimulated RetGC activity in PIGCYTg retina.