RIMS2 blocking peptide

Chemical synapses (presynaptic terminals, synaptic clefts, and postsynaptic receptors) are the neurons' communication centers. Neurotransmitters are housed in SVs. The SVs get activated, transported, docked, priming, fusion and exocytosed at the presynaptic site. Only when neurotransmitters are sent out into the synaptic cleft can electrical signals be converted into chemical ones and transmitted to the postsynaptic receptor. Neurotransmitter release is extremely complex and delicate, with a number of different molecules controlling it (SNARE complex, Munc18-1, Ca²⁺ channels). In standard central synapses, the location at the presynaptic terminal where SVs leak is called the active zone (AZ). Electron microscopy reveals that the cytomatrix in the active zone (CAZ) is a dense electron-rich substance attached to the presynaptic plasma membrane, formed by a collection of insoluble protein complexes anchored to this membrane. This assembly of protein complexes connects essential components involved in neurotransmitter release in designated areas, including Ca²⁺ channels and SNARE complexes, ensuring that the processes of vesicle docking, priming, and fusion are tightly coordinated. Key members of CAZ include RIM, RIM-BPs, ELKS/CAST, Bassoon/Piccolo, Liprin-α, and Munc13-1. Among these components, RIM (regulating synaptic membrane exocytosis protein) acts as a significant scaffold protein. Studies indicate that RIM interacts closely with other AZ proteins, influencing the anchoring and fusion of SVs while regulating neurotransmitter release and potentially altering synaptic plasticity.

Figure 1. RIM gene and protein names
(Source: Wu S, et al. 2023)

In vertebrates, RIM has four genes: RIM1, RIM2, RIM3 and RIM4. These genes code for seven RIM isoforms. Each human RIM1 gene, mouse RIM1 gene and mouse RIM2 gene are about 500kb each, and the human RIM2 gene is around 750kb. RIM is a multidomain protein featuring several domains from its N-terminus to C-terminus: an α-helical zinc finger structure, a PDZ domain, two C2 domains at the C-terminal end, and a proline-rich conserved sequence situated between the two C2 domains. The RIM2 gene may possess three independent promoters allowing for translation into RIM2α, RIM2β, and RIM2γ. Notably, RIM2β contains all domains except for the α-helical regions and zinc finger domains. In contrast, RIM2γ consists solely of a C-terminal C2 domain along with a short N-terminal flanking sequence. Among the seven protein subtypes found in vertebrates, only RIM1α and RIM2α encompass all of the RIM domains, underscoring their significant roles in living organisms.

Furthermore, RIM has been identified in pancreatic tissue. Pancreatic β cells are classic neuroendocrine cells that secrete insulin via dense core vesicles; here, RIM plays a regulatory role in insulin release. Additionally, RIM has been observed in both visual and auditory systems. A unique type of synapse known as the ribbon synapse exists within photoreceptor cells and bipolar cells in the retina as well as in vestibular hair cells of the inner ear and cochlear hair cells. Unlike conventional central synapses, ribbon synapses feature a specialized organelle within CAZ called the synaptic ribbon. This protein structure extends into the cytoplasm of the active zone and anchors numerous releasable SVs near CAZ. The ribbon synapses in both the retina and inner ear facilitate the transmission of light and sound information through neurotransmitter release. The calyx of Held located in the auditory brainstem represents a large synapse where studies have shown that its ability to recruit calcium channels is significantly diminished in mice lacking RIM. In immature inner ear hair cells within the cochlea, RIM2α contributes to maintaining Cav1.3 gating dynamics stability. Regarding vision research, researchers have discovered a mutation in RIM2 during their study on patients with CRSD.

RIM2 blocking peptide
Regulating synaptic membrane exocytosis 2 blocking peptide
Rab3-interacting molecule 2 blocking peptide
RAB3IP3 blocking peptide