Bernard Paul B, Castano Anna M, Buonarati Olivia R, Camp Chad R, Hell Johannes W, Benke Tim A
Departments of Pediatrics, University of Colorado, School of Medicine, United States of America.
Departments of Pediatrics, University of Colorado, School of Medicine, United States of America; Pharmacology, University of Colorado, School of Medicine, United States of America.
Neurobiol Dis. 2025 Jun 1;209:106884. doi: 10.1016/j.nbd.2025.106884. Epub 2025 Mar 25.
We probed the dependence of metabotropic glutamate receptor dependent long-term depression (mGluR-LTD) on L-type voltage gated calcium channels (LTCCs). In prior work, we found that in a rat model of early life seizures (ELS), exaggerated mGluR-LTD was partly mediated by LTCCs and protein phosphatase 2A (PP2A). Here, we further investigated the interactive role of LTCCs, PP2A, and protein kinase A (PKA) in this same model. PP2Ac is known to bind Ca1.2 and modulate its function; displacement of PP2A (C subunit, or PP2Ac) as well as PKA phosphorylation of Ca1.2 at serine 1928, result in enhanced Ca1.2 function. We found that ELS enhanced LTCC activity. We further found that pharmacological displacement of PP2Ac (but not PP2B/calcineurin) from Ca1.2 enhanced mGluR-LTD in controls. This was occluded by blockade of PP2A or ELS. The LTCC-dihydropyridine agonist BayK 8644 enhanced mGluR-LTD in controls, which was also occluded by ELS. Up-regulation of both intracellular Ca and PKA activity were implicated in ELS enhancement of mGluR-LTD, as LTD was normalized in ELS by depletion of internal calcium stores or blockade of PKA. These results support a dynamic model of mGluR-LTD regulation by LTCCs through PP2Ac binding and phosphorylation by PKA. This regulation is chronically lost after ELS. Together with our prior work, these studies tie hyperactive LTCCs to the chronic ELS behavioral phenotype that includes abnormal working memory, fear conditioning and socialization.
我们探究了代谢型谷氨酸受体依赖的长时程抑制（mGluR-LTD）对L型电压门控钙通道（LTCCs）的依赖性。在之前的研究中，我们发现，在早期生活性癫痫（ELS）的大鼠模型中，过度的mGluR-LTD部分是由LTCCs和蛋白磷酸酶2A（PP2A）介导的。在此，我们进一步研究了LTCCs、PP2A和蛋白激酶A（PKA）在同一模型中的相互作用。已知PP2Ac可与Ca1.2结合并调节其功能；PP2A（C亚基，即PP2Ac）的移位以及Ca1.2在丝氨酸1928处的PKA磷酸化会导致Ca1.2功能增强。我们发现ELS增强了LTCC活性。我们还发现，从Ca1.2上进行PP2Ac（而非PP2B/钙调神经磷酸酶）的药理学置换可增强对照中的mGluR-LTD。这被PP2A阻断剂或ELS所阻断。LTCC-二氢吡啶激动剂BayK 8644增强了对照中的mGluR-LTD，这也被ELS所阻断。细胞内钙和PKA活性的上调与ELS增强mGluR-LTD有关，因为通过耗尽细胞内钙库或阻断PKA可使ELS中的LTD恢复正常。这些结果支持了一种动态模型，即LTCCs通过PP2Ac结合和PKA磷酸化来调节mGluR-LTD。ELS后这种调节会长期丧失。与我们之前的研究一起，这些研究将过度活跃的LTCCs与包括异常工作记忆、恐惧条件反射和社交行为在内的慢性ELS行为表型联系起来。
