Levels of 1.2 L-Type Channels Peak in the First Two Weeks in Rat Hippocampus Whereas 1.3 Channels Steadily Increase through Development

Abstract

Influx of calcium through voltage-dependent channels regulates processes throughout the nervous system. Specifically, influx through L-type channels plays a variety of roles in early neuronal development and is commonly modulated by G-protein-coupled receptors such as GABAB receptors. Of the four isoforms of L-type channels, only CaV1.2 and CaV1.3 are predominately expressed in the nervous system. Both isoforms are inhibited by the same pharmacological agents, so it has been difficult to determine the role of specific isoforms in physiological processes. In the present study, Western blot analysis and confocal microscopy were utilized to study developmental expression levels and patterns of CaV1.2 and CaV1.3 in the CA1 region of rat hippocampus. Steady-state expression of CaV1.2 predominated during the early neonatal period decreasing by day 12. Steady-state expression of CaV1.3 was low at birth and gradually rose to adult levels by postnatal day 15. In immunohistochemical studies, antibodies against CaV1.2 and CaV1.3 demonstrated the highest intensity of labeling in the proximal dendrites at all ages studied (P1–72). Immunohistochemical studies on one-week-old hippocampi demonstrated significantly more colocalization of GABAB receptors with CaV1.2 than with CaV1.3, suggesting that modulation of L-type calcium current in early development is mediated through CaV1.2 channels.

Characterization of L-type voltage-gated Ca2+ channel expression and function in developing CA3 pyramidal neurons

“…In contrast, Ca v 1.3 levels remain relatively constant during P4-30. Our findings are similar to those of previous studies showing that Ca v 1.2 protein levels, albeit different isoforms, reach a maximum between P4-8 in the CA1 region of the rat hippocampus (Kramer et al, 2012; Nuñez and McCarthy, 2007). However, Kramer et al found that different Ca v 1.3 isoform levels progressively increase between P1 and P20 in the CA1 region, suggesting that the expression of specific isoforms is differentially regulated between the CA1 and CA3 region during postnatal development.…”

Regulation of seizure-induced MeCP2 Ser421 phosphorylation in the developing brain

“…Our in vitro findings suggest that Ca 2+ influx from LT-VGCCs and CP-AMPARs both individually contribute to MeCP2 phosphorylation, and both pathways likely converge on a common endpoint. Notably, LT-VGCCs are developmentally upregulated during early postnatal development (Kramer et al, 2012; Morton et al, 2013; Schlick et al, 2010), and have been implicated in promoting both epileptogenesis (Beck et al, 1998; Siwek et al, 2012; Speckmann et al, 1993; Stiglbauer et al, 2017) and ASD-like behavior (Jinnah et al, 1999); Ca 2+ influx-promoting mutations in LT-VGCCs cause Timothy Syndrome, a rare genetic form of ASD (Bader et al, 2011; Barrett and Tsien, 2008; Splawski et al, 2004).…”

“…In contrast to the adult, in which NMDARs primarily mediate activity-dependent, synaptically-driven Ca 2+ signaling (Zhou et al, 2006), the immature brain contains Ca 2+ -permeable, GluA2-lacking AMPARs (Talos et al, 2006a,b), which significantly contribute to developmentally relevant intracellular signaling (Cull-Candy et al, 2006; Henley and Wilkinson, 2016; Rakhade and Jensen, 2009). Furthermore, Ca V 1.2 LT-VGCC expression is also developmentally upregulated in this same period of the second postnatal week (Kramer et al, 2012; Morton et al, 2013; Schlick et al, 2010). Given the protective effects of AMPAR blockers in our early-life in vivo seizure model compared with other glutamate receptor antagonists (Jensen et al, 1995; Jensen and Wang, 1996), we asked whether over-activation of CP-AMPARs and LT-VGCCs in early-life seizures might disrupt signaling pathways relevant to neurodevelopment.…”

Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains

“…Ca influx through LTCCs regulates the phosphorylation of cAMP-responsive element-binding protein through the activation of calmodulin kinase (CAMK) and the Ras/mitogen-activated protein kinase (MAPK) signaling cascade [87,88,89]. The LTCC Ca v 1.2 is critical for cellular events during the early development of the hippocampus [90]. LTCCs have been shown to be involved in synaptic plasticity and memory processes in the hippocampus.…”