Alternative splicing plays a key role in posttranscriptional regulation of gene expression, allowing a single gene to encode multiple protein isoforms. As such, alternative splicing amplifies the coding capacity of the genome enormously, generates protein diversity, and alters protein function. More than 90% of human genes undergo alternative splicing, and alternative splicing is especially prevalent in the nervous and immune systems, tissues where cells need to react swiftly and adapt to changes in the environment through carefully regulated mechanisms of cell differentiation, migration, targeting, and activation. Given its prevalence and complexity, this highly regulated mode of gene expression is prone to be affected by disease. In the following review, we look at how alternative splicing of signaling molecules—cytokines and their receptors—changes in different pathological conditions, from chronic inflammation to neurologic disorders, providing means of functional interaction between the immune and neuroendocrine systems. Switches in alternative splicing patterns can be very dynamic and can produce signaling molecules with distinct or antagonistic functions and localization to different subcellular compartments. This newly discovered link expands our understanding of the biology of immune and neuroendocrine cells, and has the potential to open new windows of opportunity for treatment of neurodegenerative disorders.

Voltage‐gated calcium channels (VGCCs) are multi‐subunit ion channel proteins that control and regulate a wide array of physiological processes. Their dysfunction has been implicated in several neurological, cardiac, psychiatric, endocrine, oncogenic, and muscular disorders. The diverse and specialized cellular functions involving VGCC‐mediated calcium signaling stem from two primary mechanisms: differential and cell‐specific expression of pore‐forming (α1) and auxiliary subunit genes, and extensive alternative splicing of their pre‐mRNA. All the 10 α1‐encoding genes undergo alternative splicing to generate a wide array of cell‐specific CaV variants with distinct biophysical, pharmacological, and protein–protein interaction properties. This proteomic diversity and the associated cell‐specific expression signature of CaV splice variants are tightly regulated by trans‐acting splicing factors—RNA‐binding proteins that control the inclusion or skipping of alternatively spliced exons during post‐transcriptional pre‐mRNA processing. The discovery that several channelopathies are caused by aberrant splicing due to genetic mutations in either cis‐acting binding elements on the pre‐mRNA or in core splicing machinery components highlights the crucial role of alternative splicing in VGCC‐related pathologies. These insights have opened new therapeutic avenues, as targeting the alternative splicing of disease‐associated specific exons has recently emerged as a novel, promising treatment for neurodevelopmental disorders and channelopathies associated with splicing dysfunction.

Interferon-gamma (IFN-γ) is a critical cytokine that plays a pivotal role in immune system regulation. It is a key mediator of both cellular defense mechanisms and antitumor immunity. As the sole member of the type II interferon family, IFN-γ modulates immune responses by activating macrophages, enhancing natural killer cell function, and regulating gene expression across multiple cellular processes. Alternative splicing is a post-transcriptional gene expression regulatory mechanism that generates multiple mature messenger RNAs from a single gene, dramatically increasing proteome diversity without the need of a proportional genome expansion. This process occurs in 90–95% of human genes, with alternative splicing events allowing for the production of diverse protein isoforms that can have distinct—or even opposing—functional properties. Alternative splicing plays a crucial role in cancer immunology, potentially generating tumor neoepitopes and modulating immune responses. However, how alternative splicing affects IFN-γ’s activity is still poorly understood. This review explores how alternative splicing regulates the expression and function of both upstream regulators and downstream effectors of IFN-γ, revealing complex mechanisms of gene expression and immune response modulation. Key transcription factors and signaling molecules of the IFN-γ pathway are alternatively spliced, and alternative splicing can dramatically alter IFN-γ signaling, immune cell function, and response to environmental cues. Specific splice variants can enhance or inhibit IFN-γ-mediated immune responses, potentially influencing cancer immunotherapy, autoimmune conditions, and infectious disease outcomes. The emerging understanding of these splicing events offers promising therapeutic strategies for manipulating immune responses through targeted molecular interventions.