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Plasma membrane calcium ATPases and cerebellar pathology: what's the role in the ataxia?

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Title: Plasma membrane calcium ATPases and cerebellar pathology: what's the role in the ataxia?
Authors: Peggion C; Department of Biology, University of Padova, Padova, Italy., Marchionni I; Department of Biomedical Sciences (DSB), University of Padova, Padova, Italy., Carafoli E; Veneto Institute of Molecular Medicine, Padova, Italy. ernestocarafoli@gmail.com., Brini M; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy. marisa.brini@unipd.it.; Study Center for Neurodegeneration (CESNE), University of Padova, Padova, Italy. marisa.brini@unipd.it., Calì T; Department of Biomedical Sciences (DSB), University of Padova, Padova, Italy. tito.cali@unipd.it.; Study Center for Neurodegeneration (CESNE), University of Padova, Padova, Italy. tito.cali@unipd.it.; Padova Neuroscience Center (PNC), University of Padova, Padova, Italy. tito.cali@unipd.it.
Source: Biology direct [Biol Direct] 2025 Nov 06; Vol. 20 (1), pp. 109. Date of Electronic Publication: 2025 Nov 06.
Publication Type: Journal Article; Review
Language: English
Journal Info: Publisher: BioMed Central Country of Publication: England NLM ID: 101258412 Publication Model: Electronic Cited Medium: Internet ISSN: 1745-6150 (Electronic) Linking ISSN: 17456150 NLM ISO Abbreviation: Biol Direct Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : BioMed Central, 2006-
MeSH Terms: Plasma Membrane Calcium-Transporting ATPases*/metabolism , Plasma Membrane Calcium-Transporting ATPases*/genetics , Cerebellum*/pathology , Cerebellum*/enzymology , Cerebellar Ataxia*/enzymology, Humans ; Animals ; Calcium/metabolism ; Calcium Signaling ; Cell Membrane/enzymology ; Neurons/metabolism
Abstract: Competing Interests: Declarations. Competing interests: The authors declare no competing interests.
Ca²⁺ signaling is essential for neuronal development, migration, synaptic activity, spine plasticity, neurotransmitter release, membrane excitability, and long-term synaptic plasticity, as well as for the coupling between membrane depolarization and downstream signaling. Traditionally, Plasma Membrane Ca²⁺ ATPases (PMCAs) were considered high-affinity, low-capacity calcium extruders. However, recent evidence reveals that the PMCA-Neuroplastin complex facilitates ultrafast Ca²⁺ clearance at kilohertz frequencies, reshaping our understanding of calcium regulation, in particular in neurons. For bulk Ca²⁺ clearance, they are overshadowed by more powerful low-affinity/high-capacity systems on the plasma membrane. This raises key questions: what is the specific physiological and pathological role of PMCAs? Why do cells require a high-affinity/low-capacity, ATP-dependent extrusion mechanism? What is the functional meaning of the diversity of isoforms (four) and splice variants (over thirty)? And why do neurons localize distinct PMCA pumps to pre- and postsynaptic sites? The prevailing hypothesis is that PMCAs fine-tune Ca²⁺ microdomains through local regulation and interactions with specific protein partners. Finally, understanding their role in Purkinje cells (PCs) is particularly relevant, as alterations in PMCA function have been implicated in cerebellar pathology and ataxia.
(© 2025. The Author(s).)
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Contributed Indexing: Keywords: Ca2+ microdomains.; Ca2+ signaling; Cerebellar ataxia; Plasma membrane calcium ATPases
Substance Nomenclature: EC 3.6.3.8 (Plasma Membrane Calcium-Transporting ATPases)
SY7Q814VUP (Calcium)
Entry Date(s): Date Created: 20251106 Date Completed: 20251107 Latest Revision: 20251110
Update Code: 20251110
PubMed Central ID: PMC12590814
DOI: 10.1186/s13062-025-00702-2
PMID: 41199322
Database: MEDLINE
Description
Abstract:Competing Interests: Declarations. Competing interests: The authors declare no competing interests.<br />Ca²⁺ signaling is essential for neuronal development, migration, synaptic activity, spine plasticity, neurotransmitter release, membrane excitability, and long-term synaptic plasticity, as well as for the coupling between membrane depolarization and downstream signaling. Traditionally, Plasma Membrane Ca²⁺ ATPases (PMCAs) were considered high-affinity, low-capacity calcium extruders. However, recent evidence reveals that the PMCA-Neuroplastin complex facilitates ultrafast Ca²⁺ clearance at kilohertz frequencies, reshaping our understanding of calcium regulation, in particular in neurons. For bulk Ca²⁺ clearance, they are overshadowed by more powerful low-affinity/high-capacity systems on the plasma membrane. This raises key questions: what is the specific physiological and pathological role of PMCAs? Why do cells require a high-affinity/low-capacity, ATP-dependent extrusion mechanism? What is the functional meaning of the diversity of isoforms (four) and splice variants (over thirty)? And why do neurons localize distinct PMCA pumps to pre- and postsynaptic sites? The prevailing hypothesis is that PMCAs fine-tune Ca²⁺ microdomains through local regulation and interactions with specific protein partners. Finally, understanding their role in Purkinje cells (PCs) is particularly relevant, as alterations in PMCA function have been implicated in cerebellar pathology and ataxia.<br /> (© 2025. The Author(s).)
ISSN:1745-6150
DOI:10.1186/s13062-025-00702-2