{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe presynaptic active zone is orchestrated by a network of proteins that ensure the proper timing and extent of neurotransmitter release. In these studies, proteins belonging to the CAST/ELKS family are shown to tightly regulate synaptic vesicle availability and release dynamics. For example, deletion of the active zone protein ELKS2α in mice led to an increase in inhibitory, but not excitatory, transmitter release by enlarging the readily releasable pool of vesicles without altering most ultrastructural features of synapses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of specialized synapses, such as in rod photoreceptors, the depletion of CAST results in smaller active zones with reduced Ca²⁺ channel clustering and overall diminished release capacity. This structural scaling of the release machinery, manifesting in both impaired rod transmitter release and decreased visual sensitivity, underscores the importance of active zone size in controlling transmission rates."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, CAST interacts directly with voltage-dependent Ca²⁺ channels, with its association (notably via the VDCC β₄-subunit) modifying the channels’ biophysical properties, such as shifting their voltage dependence toward hyperpolarized potentials. These alterations likely contribute to fine-tuning calcium influx in response to depolarization and thereby regulating neurotransmitter release."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional layers of regulation come from posttranslational modifications of CAST, as evidenced by phosphorylation by the protein kinase SAD-B. Phosphorylation of a specific N-terminal residue on CAST modulates the rate at which the readily releasable pool is replenished, thereby controlling short-term synaptic depression. Phosphomimetic and phosphonull variants of CAST produce opposing effects on this vesicle reloading process, indicating a precise, activity-dependent regulatory mechanism at the nerve terminal."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, CAST plays a dual role by not only influencing the dynamics of vesicle recycling after endocytosis but also by stabilizing the neurotransmitter content (quantal size) in synaptic vesicles. This dual function is critical for maintaining synaptic efficacy during prolonged activity and preventing excessive synaptic depression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, coordinated function between CAST and ELKS is essential for proper neurotransmission, as demonstrated in forebrain synapses. While CAST is dominant, ELKS is capable of partially supporting its function. Nonetheless, simultaneous deletion of both proteins disrupts the integrity of sensory-to-motor networks, culminating in severe behavioral deficits such as impaired exploration and failure to suckle in neonatal mice."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIt is important to note that none of the provided abstracts directly address the function of RBMY1E. Instead, they focus on the roles of CAST/ELKS proteins in regulating presynaptic active zone architecture and neurotransmitter release. Therefore, the functional insights summarized here pertain specifically to the CAST/ELKS protein network rather than RBMY1E.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Pascal S Kaeser, Lunbin Deng, Andrés E Chávez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ELKS2alpha/CAST deletion selectively increases neurotransmitter release at inhibitory synapses."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuron (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.neuron.2009.09.019"}], "href": "https://doi.org/10.1016/j.neuron.2009.09.019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19874790"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19874790"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Susanne tom Dieck, Dana Specht, Nicola Strenzke, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deletion of the presynaptic scaffold CAST reduces active zone size in rod photoreceptors and impairs visual processing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.0752-12.2012"}], "href": "https://doi.org/10.1523/JNEUROSCI.0752-12.2012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22933801"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22933801"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Shigeki Kiyonaka, Hiroshi Nakajima, Yoshinori Takada, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Physical and functional interaction of the active zone protein CAST/ERC2 and the β-subunit of the voltage-dependent Ca(2+) channel."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biochem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/jb/mvs054"}], "href": "https://doi.org/10.1093/jb/mvs054"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22577167"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22577167"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Sumiko Mochida, Yamato Hida, Shota Tanifuji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SAD-B Phosphorylation of CAST Controls Active Zone Vesicle Recycling for Synaptic Depression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2016.08.020"}], "href": "https://doi.org/10.1016/j.celrep.2016.08.020"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27626661"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27626661"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Shizuka Kobayashi, Yamato Hida, Hiroyoshi Ishizaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The active zone protein CAST regulates synaptic vesicle recycling and quantal size in the mouse hippocampus."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Neurosci (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/ejn.13331"}], "href": "https://doi.org/10.1111/ejn.13331"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27422015"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27422015"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Akari Hagiwara, Shun Hamada, Yamato Hida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Double deletion of the active zone proteins CAST/ELKS in the mouse forebrain causes high mortality of newborn pups."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Brain (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13041-020-0557-x"}], "href": "https://doi.org/10.1186/s13041-020-0557-x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31996256"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31996256"}]}]}]}