HPCAL4

HPCAL4 Full Name

hippocalcin like 4

HPCAL4 Introduction

Hippocalcin-like protein 4 (HPCAL4), also known as neurocalcin delta or visinin-like protein 3 (VILIP-3), is a member of the neuronal calcium sensor (NCS) family of EF-hand calcium-binding proteins. Encoded by the HPCAL4 gene on chromosome 1p34.3, HPCAL4 is predominantly expressed in the central nervous system, particularly in cerebellar Purkinje cells, striatal neurons, and subsets of hippocampal and cortical neurons. Like other NCS family members, HPCAL4 contains four EF-hand calcium-binding motifs (three functional and one non-functional) and an N-terminal myristoylation site that facilitates its calcium-dependent membrane association.

Figure 1. HPCAL4 (Hippocalcin-like Protein 4): A Neuronal Calcium Sensor Gene.

Calcium-Dependent Signaling and Subcellular Dynamics
HPCAL4 undergoes a pronounced conformational change upon calcium binding, which exposes its N-terminal myristoyl group and promotes translocation from the cytosol to cellular membranes — a mechanism known as the calcium-myristoyl switch that is characteristic of the NCS protein family. Once membrane-associated, HPCAL4 modulates the activity of several downstream effectors including guanylyl cyclase-activating proteins and ion channels. HPCAL4 also interacts with the actin cytoskeleton through its association with filamentous actin, potentially linking calcium signaling to cytoskeletal reorganization in neuronal processes. Unlike its close relative hippocalcin, HPCAL4 exhibits slower calcium dissociation kinetics, allowing it to integrate calcium signals over longer time scales and respond to sustained rather than transient calcium elevations.

HPCAL4 in Neuronal Function and Neurodegenerative Disease
HPCAL4 contributes to the regulation of synaptic plasticity and neuronal excitability in specific brain circuits. In striatal medium spiny neurons, HPCAL4 modulates dopamine receptor signaling pathways, with implications for motor control and reward processing. HPCAL4 expression is altered in several neurological conditions: it is downregulated in the striatum of Huntington's disease patients and mouse models, potentially contributing to the synaptic dysfunction that characterizes early disease stages. In Alzheimer's disease, HPCAL4 (as VILIP-3) levels in cerebrospinal fluid have been investigated as a potential biomarker for neuronal injury. The calcium-sensing properties of HPCAL4 also position it as a potential mediator of calcium dyshomeostasis-related neurotoxicity in excitotoxic and ischemic brain injury. Further elucidation of the specific HPCAL4 interactome may reveal novel therapeutic targets for neurodegenerative and movement disorders.

Alternate Names for HPCAL4

HPCAL4; hippocalcin like 4; hippocalcin-like protein 4; DKFZp761G122; HLP4;