ACRC

ACRC Full Name

acidic repeat containing

ACRC Introduction

ACRC, also known as ASIC2/3 regulatory protein or protein kinase C and casein kinase substrate in neurons (PACSIN) family member, is a protein involved in the trafficking and functional modulation of acid-sensing ion channels (ASICs) in the nervous system. The human ACRC gene is located on chromosome 10q24.32, spans approximately 15 kb, and contains 7 exons encoding a 487-amino-acid protein with a molecular weight of approximately 55 kDa. ACRC was originally identified through its interaction with the carboxy-terminal domains of ASIC2 and ASIC3, two subunits of the acid-sensing ion channel family that detect extracellular pH drops and mediate neuronal responses to tissue acidosis. Beyond its role in ASIC regulation, ACRC has been implicated in synaptic vesicle recycling, cytoskeletal organization, and neuronal differentiation, making it a multifunctional adaptor protein in the central and peripheral nervous systems. The protein contains several conserved domains, including an N-terminal F-BAR (FCH-BAR) domain that mediates membrane curvature sensing and tubulation, and a C-terminal SH3 (Src homology 3) domain that binds proline-rich motifs in interacting partners. ACRC is predominantly expressed in neurons, with highest levels detected in the brain (particularly the hippocampus, cerebral cortex, cerebellum, and amygdala) and dorsal root ganglia (DRG), with lower expression in the spinal cord and peripheral tissues. Its expression pattern and binding partners suggest that ACRC serves as a molecular scaffold linking ion channels to the endocytic machinery and the actin cytoskeleton, thereby controlling channel surface expression, subcellular localization, and functional properties.

Figure 1.The structure of ACRC.

Tissue Distribution and Subcellular Localization
ACRC expression is highly enriched in the nervous system, with negligible expression in non-neuronal tissues such as liver, kidney, heart, and skeletal muscle. Within the brain, in situ hybridization and immunohistochemical studies reveal that ACRC mRNA and protein are most abundant in the hippocampus (particularly in pyramidal neurons of the CA1-CA3 subfields and granule cells of the dentate gyrus), the cerebral cortex (layers II-VI), the amygdala, the striatum, and the cerebellum (Purkinje cells and granule cells). In the peripheral nervous system, ACRC is expressed in dorsal root ganglion neurons, where it colocalizes with ASIC2 and ASIC3 in small-to-medium diameter neurons that are known to be involved in nociception (pain sensation). At the subcellular level, ACRC localizes to the cytoplasm and is enriched at sites of membrane remodeling, including the plasma membrane, endosomes, and the trans-Golgi network. The F-BAR domain of ACRC binds to phosphoinositide-rich membranes and induces membrane tubulation, a process essential for endocytosis and endosomal trafficking. In cultured hippocampal neurons, ACRC is found in dendritic spines, where it may regulate the trafficking of ASICs and other receptors to the postsynaptic membrane. Additionally, ACRC interacts with the actin cytoskeleton via its SH3 domain-mediated binding to dynamin and other actin-regulatory proteins, anchoring signaling complexes to specific subcellular compartments.

Role in Synaptic Vesicle Recycling and Endocytosis
Beyond its role in ion channel regulation, ACRC participates in synaptic vesicle recycling, a process essential for maintaining neurotransmitter release during sustained neuronal activity. The F-BAR domain of ACRC binds to membranes with high curvature and induces tubulation, which is required for the formation of endocytic vesicles from the plasma membrane. ACRC interacts with dynamin, a large GTPase that pinches off nascent vesicles from the membrane, through a proline-rich motif in the linker region between the F-BAR and SH3 domains. This interaction recruits dynamin to sites of endocytosis and coordinates the fission step. In hippocampal neurons, knockdown of ACRC reduces the rate of synaptic vesicle endocytosis following electrical stimulation, leading to depletion of the recycling vesicle pool and impaired synaptic transmission during high-frequency stimulation. ACRC also binds to synaptojanin-1, a polyphosphoinositide phosphatase that dephosphorylates PIP2 to terminate endocytic events, suggesting that ACRC acts as a scaffold that coordinates multiple proteins in the endocytic machinery. The functional importance of ACRC in synaptic vesicle cycling is underscored by the observation that mice lacking ACRC (Acrc knockout) exhibit depressed synaptic transmission in hippocampal slices and show deficits in hippocampal-dependent learning and memory tasks, including contextual fear conditioning and novel object recognition.

Alternate Names for ACRC

ACRC; acidic repeat containing; acidic repeat-containing protein; putative nuclear protein; NAAR1;