Neuronal calcium signaling: Mechanisms, function and clinical implications in neurological diseases

The neuronal calcium signaling plays a pivotal role in maintaining neuronal function and orchestrating neural network activity. As a key second messenger, calcium ions (Ca²⁺) participate in a broad spectrum of intra- and extracellular signaling processes, influencing essential physiological functions such as synaptic transmission, neuronal excitability, gene expression, and cell fate determination. This review aims to provide an overview of the fundamental mechanisms underlying neuronal calcium signaling, including the sources and regulation of intracellular calcium, the associated signaling cascades, and their termination pathways. Furthermore, it will analyze the specific functional roles of calcium signaling in neurons and elucidate its intricate regulatory mechanisms, including the involvement of calcium channels and receptors, calcium-binding proteins, and calcium pumps and exchangers. Particular emphasis will be placed on the implications of calcium signaling dysregulation in neurological diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and epilepsy. In addition, this review will examine emerging clinical applications of targeting calcium signaling pathways, including the development of pharmacological modulators and the identification of novel diagnostic and therapeutic targets. By integrating recent research advances and theoretical developments, this review seeks to offer a detailed and up-to-date understanding of the critical role of calcium signaling in neuroscience and its translational relevance to clinical practice.