GNB5 (G protein subunit beta 5) is a critical component of G protein-coupled receptor (GPCR) signaling that enhances the GTPase-activating protein activity of RGS proteins, particularly RGS7 and RGS9, thereby terminating GPCR-initiated signaling by accelerating GTP hydrolysis on G-alpha subunits 1. This function is essential for dopamine receptor signaling deactivation and mood/cognition regulation. GNB5 also plays an important role in parasympathetic cardiac control [UniProt]. Beyond canonical GPCR signaling, GNB5 acts as a negative regulator of BACE1-mediated amyloid-beta generation, with its WD domain and Ser81 residue being critical for this regulatory function 2. Loss-of-function GNB5 variants cause Lodder-Merla syndrome (types 1 and 2), characterized by intellectual disability, sinus bradycardia, hypotonia, visual abnormalities, and epilepsy 34. GNB5-related encephalopathy predominantly presents with epileptic spasms (occurring in 89% of cases), focal seizures, profound developmental impairment, and cardiac arrhythmias 5. Recent evidence suggests GNB5 dysfunction may contribute to Alzheimer's disease pathogenesis through impaired BACE1 regulation 2, and GNB5 mutations represent a non-ion channel genetic basis for combined epilepsy-arrhythmia comorbidity 6.