Work

PKA restricts ERK signaling in learning and memory Kenyon cell neurons

Year: 2025

Type: article

Abstract: Protein Kinase A (PKA) and Extracellular Signal-Regulated Kinase (ERK) have core roles in learning and memory. Here, we investigate kinase-kinase signaling interactions in the Drosophila brain Kenyon cell learning/memory circuit using separation of phases-based activity reporter of kinase (SPARK) biosensors to image circuit-localized functions in vivo. We find that constitutively active Rapidly Accelerated Fibrosarcoma (RAF gof ) enhances ERK signaling only in Kenyon cell domains with low baseline PKA signaling, and that transgenic inhibition of PKA function elevates ERK signaling. Conversely, loss of ERK has no impact on PKA signaling, whereas RAF gof expands PKA signaling. Importantly, transgenic PKA inhibition together with RAF gof synergistically elevates ERK signaling. These findings indicate a negative PKA-ERK pathway interaction within learning/memory Kenyon cells. We find that potentiating circuit activity using an exogenous NaChBac ion channel elevates PKA signaling in circuit domains with low baseline PKA function, and uniformly strongly increases ERK signaling. Similarly, thermogenetic stimulation of circuit activity with a temperature-sensitive TRPA1 channel increases PKA signaling in circuit domains of low baseline PKA, and elevates ERK signaling. Importantly, potentiating circuit activity (NaChBac) while also inhibiting PKA function synergistically elevates ERK signaling. Likewise, conditional induction of circuit activity (TRPA1) together with PKA inhibition increases activity-dependent ERK signaling. Finally, a mechanically-induced seizure model (bang-sensitive sesB mutant) elevates PKA signaling, while simultaneous transgenic PKA inhibition in this model acts to synergistically increase ERK signaling. Taken together, we conclude PKA limits ERK signaling in Kenyon cells within the learning and memory circuit, with PKA function acting to restrict activity-dependent ERK signaling.

Source: Cellular Signalling

DOI: 10.1016/j.cellsig.2025.111818

Authors: James C. Sears, Kendal Broadie

Institutions: Vanderbilt University, Vanderbilt University Medical Center

Language: English

Topic: Neurobiology and Insect Physiology Research

Subfield: Cellular and Molecular Neuroscience

Field: Neuroscience

Domain: Life Sciences

Open Access status: hybrid

Estimated APC paid: $3,550