Neuronal calcium sensors emerge as novel adenylyl cyclase 8 regulators

Khanppnavar, B.; Florea, R.; Schuster, D.; Lavriha, P.; Kosturanova, A.; Ruckstuhl, M. M.; Kantarci, I.; Vaithia, A.; Shi, J.; Picotti, P.; Gossert, A. D.; Leitner, A.; Korkhov, V. M.

doi:10.64898/2026.04.19.719435

bioRxiv · 10.64898/2026.04.19.719435

Neuronal calcium sensors emerge as novel adenylyl cyclase 8 regulators

Khanppnavar, B.·Florea, R.·Schuster, D.·Lavriha, P.·Kosturanova, A.·Ruckstuhl, M. M.·Kantarci, I.·Vaithia, A.·Shi, J.·Picotti, P.·Gossert, A. D.·Leitner, A.·Korkhov, V. M.

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Abstract

Adenylyl cyclase 8 (AC8) is a Ca2+-sensitive membrane adenylyl cyclase highly expressed in the central nervous system. AC8-mediated intracellular cyclic adenosine monophosphate (cAMP) accumulation shapes synaptic function, plasticity, and memory formation and is tightly controlled by intracellular Ca2+ and G protein-coupled receptor signaling. Although it is well known that the effects of Ca2+ on AC8 activity are directly mediated by calmodulin, it has remained unclear until now whether other Ca2+-binding proteins also regulate AC8 function. Here, we identify the neuronal calcium sensor hippocalcin-like protein 1 (HPCAL1) as a direct interaction partner of AC8. Using biochemistry, structural proteomics, integrative modeling, cryo-EM and cell-based FRET approaches, we show that HPCAL1 associates with AC8 in a Ca2+-dependent manner. HPCAL1 shows weak positive modulation of AC8 activity in vitro, with sub micromolar affinity. HPCAL1 interacts with flexible regulatory regions of AC8, including the C1b domain and the N- and C-terminal regions. Interestingly, other members of the neuronal calcium sensor family can bind AC8 via the same sites. Together, our study reveals a previously unrecognized mode of Ca2+-dependent AC8 recognition by a group of neuronal calcium sensor proteins, which may be relevant to context-dependent regulation of cAMP signaling.

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Khanppnavar, B., Florea, R., Schuster, D., Lavriha, P., Kosturanova, A., Ruckstuhl, M. M., Kantarci, I., Vaithia, A., Shi, J., Picotti, P., Gossert, A. D., Leitner, A., Korkhov, V. M.. 2026-04-21. Neuronal calcium sensors emerge as novel adenylyl cyclase 8 regulators. https://doi.org/10.64898/2026.04.19.719435

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