Enhanced cGMP Interactor Rap Guanine Exchange Factor 4 (EPAC2) Expression and Activity in Degenerating Photoreceptors: : A Neuroprotective Response?

Rasmussen, MichelLund University,Lunds universitet,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Department of Clinical Sciences, Lund,Faculty of Medicine (author)

The disease retinitis pigmentosa (RP) leads to photoreceptor degeneration by a yet undefined mechanism(s). In several RP mouse models (i.e., rd mice), a high cyclic GMP (cGMP) level within photoreceptors is detected, suggesting that cGMP plays a role in degeneration. The rap guanine exchange factor 4 (EPAC2) is activated by cyclic AMP (cAMP) and is an accepted cGMP-interacting protein. It is unclear whether and how cGMP interacts with EPAC2 in degenerating photoreceptors; we therefore investigated EPAC2 expression and interactions with cGMP and cAMP in retinas of the rd1 and rd10 models for retinal degeneration. EPAC2 expression in the photoreceptor layer increased significantly during rd1 and rd10 degeneration, and an increase in EPAC2 interactions with cGMP but not cAMP in the rd1 was also seen via a proximity ligation assay on histological sections. Retinal explant cultures revealed that pharmacological inhibition of the EPAC2 activity reduced the photoreceptor layer thickness in the rd10 retina, suggesting that EPAC2 inhibition promotes degeneration. Taken together, our results support the hypothesis that high degeneration-related cGMP leads to increased EPAC2 and cGMP interactions, inhibiting EPAC2. By inference, EPAC2 could have neuroprotective capacities that may be exploited in the future.

Zhou, JiamingLund University,Lunds universitet,Oftalmologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Ophthalmology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)ji6872zh (author)
Schwede, FrankBIOLOG Life Science Institute (author)
Ekström, PerLund University,Lunds universitet,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)zoof-pek (author)
Institutionen för kliniska vetenskaper, LundMedicinska fakulteten (creator_code:org_t)

By the author/editor: Rasmussen, Miche ...; Zhou, Jiaming; Schwede, Frank; Ekström, Per

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Ophthalmology

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

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