A neuron type-specific microexon in Ank3/ankyrin-G modulates calcium activity and neuronal excitability
Recent studies have revealed many alternative exons differentially spliced across diverse neuron types in the mammalian brain, but their links to neuronal physiology remain unclear. Here we characterize a deeply conserved microexon E35a in Ank3 encoding ankyrin-G (AnkG), a multifaceted adaptor protein best known as a master organizer of the axon initial segment (AIS) and as a leading genetic risk factor for bipolar disorder. E35a is predominantly skipped in cortical glutamatergic neurons but included in cortical GABAergic neurons and cerebellar neurons, which is dictated by multiple neuronal splicing factors. In E35a-deletion mice we generated, interneurons show increased excitability and somatic Ca<sup>2+</sup> activity, without disruption in AIS. Biochemical analyses suggest that E35a inclusion facilitates AnkG interaction with a protein complex involving inositol trisphosphate receptors (InsP3Rs) important for intracellular Ca<sup>2+</sup> signaling. Alternative splicing therefore allows AnkG to modulate neuron type-specific excitability in addition to its ubiquitous pan-neuronal role in organizing the AIS.
Authors
- Elizabeth Valenzuela
- 李淼
- Yow-Tyng Yeh (ORCID: https://orcid.org/0000-0002-3865-8102)
- Melissa Campbell (ORCID: https://orcid.org/0000-0002-6265-8882)
- Neil L. Harrison (ORCID: https://orcid.org/0000-0002-8013-7765)
- Mu Yang (ORCID: https://orcid.org/0000-0001-7084-029X)
- Elizabeth E. Rafikian
- Tulsi Patel (ORCID: https://orcid.org/0000-0002-2797-1443)
- Chaolin Zhang (ORCID: https://orcid.org/0000-0002-0013-5314)
- Sheng-Han Kuo
- Clarissa L. Waites (ORCID: https://orcid.org/0000-0003-4263-5576)
- Dmytro Ustianenko
- Marko Jovanović (ORCID: https://orcid.org/0000-0001-9707-3377)
- Ilaria Balbo (ORCID: https://orcid.org/0000-0001-9918-6711)
- Marianna Zazhytska (ORCID: https://orcid.org/0000-0002-6874-8272)
- Brian Joseph (ORCID: https://orcid.org/0000-0001-9876-0021)
- Stavros Lomvardas (ORCID: https://orcid.org/0000-0002-7668-3026)
- Yueqing Peng (ORCID: https://orcid.org/0000-0002-3488-0670)
- Georgia Dermentzaki
- Ruizhi Wang (ORCID: https://orcid.org/0000-0003-2535-9944)
- Chyuan-Sheng Lin
- Shah Alam
- David Cabrera-Garcia
- Helene Lovett
- Lizhen Chen
- Rui Yang
- Hynek Wichterle
- Edmund Au
- Min Li
- Lia Min
- Huijuan Feng
- Xiaojian Wang
- Brittany L. Phillips
- Guang Yang
- Paul M. Jenkins
- Jessica Estrada
- Susan Brenner-Morton
Institutions
- Rutgers, The State University of New Jersey (US)
- Netherlands Institute for Neuroscience (NL)
- Fudan University (CN)
- University of Michigan (US)
- Columbia University Irving Medical Center (US)
- Johnson University (US)
- University of California San Diego (US)
- Longevity Biotech (United States) (US)
- Precision for Medicine (United States) (US)
- Synapse (Netherlands) (NL)
- Flagship Pioneering (United States) (US)
- Columbia University (US)
- Xi'an Jiaotong University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-13
- DOI
- https://doi.org/10.1038/s41467-026-69486-x
- Primary Topic
- Neurogenesis and neuroplasticity mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- National Institutes of Health