Work

A Review of the Roles of Calcium Signaling and Homeostasis in Nicotine Addiction: A Mechanistic Hypothesis Involving ATP2B2/PMCA2 and α7-Nicotinic Acetylcholine Receptors

Year: 2026

Type: review

Abstract: Calcium (Ca²⁺) signaling is essential for neurotransmitter release, synaptic plasticity, gene expression, and neuronal excitability. Nicotine, the addictive component of tobacco, activates nicotinic acetylcholine receptors (nAChRs), including alpha4ß2- and a7-containing receptor subtypes, thereby altering neuronal Ca²⁺ entry. ATP2B2 encodes plasma membrane calcium-transporting ATPase 2 (PMCA2), a neuronal high-affinity Ca²⁺ extrusion pump that helps shape local Ca²⁺ microdomains. Published work has shown that PMCA2 functionally associates with a7-nicotinic acetylcholine receptors (alpha7-nAChRs) through postsynaptic density protein 95 (PSD-95) and can influence a7-nAChR surface expression. Genetic and transcriptomic studies have also linked ATP2B2-related pathways to substance use phenotypes, but there is no direct evidence that chronic nicotine alters PMCA2 expression. This narrative review distinguishes established findings from indirect evidence and untested predictions. We propose a mechanistic hypothesis in which chronic nicotine exposure may establish a new calcium-homeostatic equilibrium characterized by alpha7-nAChR downregulation and compensatory PMCA2 upregulation. We also hypothesize that, during early withdrawal, persistently elevated PMCA2 activity could contribute to excessive Ca²⁺ extrusion, reduced presynaptic glutamate release, cognitive impairment, and relapse vulnerability. These predicted effects require direct testing in nicotine exposure and withdrawal models. This review aims to examine the roles of calcium signaling and homeostasis in nicotine addiction, with particular emphasis on ATP2B2, which encodes the calcium ion pump PMCA2, and alpha7-nAChR.

Source: Medical Science Monitor

DOI: 10.12659/msm.954223

Authors: Tingting Wang, Xuemei Liang, Bo Xiang, Lanyang Gao, Kezhi Liu

Institutions: Southwest Medical University, Affiliated Hospital of Southwest Medical University

Language: English

Topic: Nicotinic Acetylcholine Receptors Study

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Funders: Department of Science and Technology of Sichuan Province, Southwest Medical University