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Volume 26
Issue 22
10.3390/ijms262211200
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

The Mechanism of LTXN4C-Induced Ca2+ Influx Involves Latrophilin-Mediated Activation of Cav2.x Channels

by
Jennifer K. Blackburn
1,†,
John-Paul Silva
2,‡,
Evelina Petitto
1,§,
Dietmar Cholewa
3,
Elizaveta Fasler-Kan
3,
Kirill E. Volynski
2,‖ and
Yuri A. Ushkaryov
1,2,*
1
Medway School of Pharmacy, University of Kent, Chatham ME4 4TB, UK
2
Department of Biological Sciences, Imperial College London, London SW7 2AZ, UK
3
Department of Pediatric Surgery, Inselspital Bern, University of Bern, CH-3010 Bern, Switzerland
*
Author to whom correspondence should be addressed.
†
Current address: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA.
‡
Current address: Merck Sharp & Dohme (UK) Limited, UK Discovery Biologics, London, EC2M 6UR, UK.
§
Current address: Ashfield MedComms, Macclesfield SK11 7HQ, UK.
‖
Current address: UCL Institute of Neurology, University College London, London WC1N 3BG, UK.
Int. J. Mol. Sci. 2025, 26(22), 11200; https://doi.org/10.3390/ijms262211200 (registering DOI)
Submission received: 28 October 2025 / Accepted: 17 November 2025 / Published: 19 November 2025
(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Neurobiology)
Versions Notes

Abstract

Store-operated Ca2+ entry (SOCE) is a key regulator of cytosolic Ca2+ (Ca2+cyt). Presynaptic SOCE can be activated by ligands like α-latrotoxin, which acts through the presynaptic G-protein-coupled receptor latrophilin-1 (LPHN1), inducing Ca2+ influx and neurotransmitter release. To understand how SOCE-associated proteins contribute to LPHN1 signaling in neurons, we used mouse neuroblastoma NB2a cells as a genetically tractable neuronal model. The cells were stably transfected with exogenous LPHN1 or its non-signaling mutant and stimulated with the non-pore-forming α-latrotoxin mutant LTXN4C, a known trigger of neurotransmitter release. LPHN1 expression increased the proportion of neuron-like cells and upregulated the voltage-gated Ca2+ channels Cav1.2 and Cav2.1. LPHN1 stimulation by LTXN4C induced a small Ca2+ release sensitive to thapsigargin, and a strong, gradual influx of Ca2+, which was insensitive to thapsigargin. Single-cell imaging revealed that this influx consisted of desynchronized high-amplitude Ca2+ oscillations in individual cells. This response was reduced by Orai2 knockdown and completely blocked by the Cav2.1/2.2 inhibitor ω-conotoxin MVIIC. We conclude that LPHN1 activation by LTXN4C primes Ca2+ stores and induces the opening of Cav2.1/2.2 channels. These channels mediate an initial Ca2+ influx that triggers Ca2+-induced Ca2+ release and SOCE. This mechanism, elucidated in model cells, can explain how LTXN4C stimulates neurotransmitter release.
Keywords: latrophilin; ADGRL1; LTXN4C; store-operated calcium entry; voltage-gated calcium channels; fluorescent microscopy; Fluo-4; GCaMP latrophilin; ADGRL1; LTXN4C; store-operated calcium entry; voltage-gated calcium channels; fluorescent microscopy; Fluo-4; GCaMP

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MDPI and ACS Style

Blackburn, J.K.; Silva, J.-P.; Petitto, E.; Cholewa, D.; Fasler-Kan, E.; Volynski, K.E.; Ushkaryov, Y.A. The Mechanism of LTXN4C-Induced Ca2+ Influx Involves Latrophilin-Mediated Activation of Cav2.x Channels. Int. J. Mol. Sci. 2025, 26, 11200. https://doi.org/10.3390/ijms262211200

AMA Style

Blackburn JK, Silva J-P, Petitto E, Cholewa D, Fasler-Kan E, Volynski KE, Ushkaryov YA. The Mechanism of LTXN4C-Induced Ca2+ Influx Involves Latrophilin-Mediated Activation of Cav2.x Channels. International Journal of Molecular Sciences. 2025; 26(22):11200. https://doi.org/10.3390/ijms262211200

Chicago/Turabian Style

Blackburn, Jennifer K., John-Paul Silva, Evelina Petitto, Dietmar Cholewa, Elizaveta Fasler-Kan, Kirill E. Volynski, and Yuri A. Ushkaryov. 2025. "The Mechanism of LTXN4C-Induced Ca2+ Influx Involves Latrophilin-Mediated Activation of Cav2.x Channels" International Journal of Molecular Sciences 26, no. 22: 11200. https://doi.org/10.3390/ijms262211200

APA Style

Blackburn, J. K., Silva, J.-P., Petitto, E., Cholewa, D., Fasler-Kan, E., Volynski, K. E., & Ushkaryov, Y. A. (2025). The Mechanism of LTXN4C-Induced Ca2+ Influx Involves Latrophilin-Mediated Activation of Cav2.x Channels. International Journal of Molecular Sciences, 26(22), 11200. https://doi.org/10.3390/ijms262211200

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