Increased phosphorylation of the neuronal L-type Ca ²⁺ channel Ca _v 1.2 during aging

Abstract

An increase in Ca 2؉ influx through L-type Ca 2؉ channels is thought to contribute to neuronal dysfunctions that underlie senile symptoms and Alzheimer's disease. The molecular basis of the agedependent up-regulation in neuronal L-type Ca 2؉ channel activity is largely unknown. We show that phosphorylation of the L-type channel Ca v1.2 by cAMP-dependent protein kinase is increased >2-fold in the hippocampus of aged rats. The hippocampus is critical for learning and is one of the first brain regions to be affected in Alzheimer's disease. Phosphorylation of Ca v1.2 by cAMP-dependent protein kinase strongly enhances its activity. Therefore, increased Ca v1.2 phosphorylation may account for a substantial portion of the age-related rise in neuronal Ca 2؉ influx and its neuropathological consequences. C a 2ϩ regulates a variety of signaling pathways (1-3). Acute uncontrolled Ca 2ϩ influx can cause neuronal death by overstimulation of the N-methyl-D-aspartate (NMDA)-type glutamate receptor (4, 5). Chronic elevation of Ca 2ϩ influx has been implicated in age-associated neuronal loss and Alzheimer's disease (6, 7). The age-related learning impairment in rabbits is reversed by the specific L-type Ca 2ϩ channel blocker nimodipine (8). These observations indicate that elevation of L-type channel activity causes neuronal dysfunction during aging. Ca 2ϩ influx through L-type channels is up-regulated Ͼ2-fold in hippocampal neurons of old versus adult rats (9). The hippocampus is crucial for learning and memory; however, the molecular basis for the increase in L-type channel activity during aging is not well defined, except for an Ϸ20% increase in Ca v 1.3 protein (10, 11). We now show that cAMP-dependent protein kinase (PKA)-mediated phosphorylation of the L-type channel Ca v 1.2 increases Ͼ2-fold during aging and that it may underlie a substantial portion of the age-related increase in L-type channel activity.PKA increases L-type channel activity in neurons (13-16) and in the heart, where PKA-dependent stimulation of the cardiac L-type channel is crucial for the up-regulation of the heartbeat after adrenergic stimulation (17, 18 (19), and the auxiliary subunits ␣ 2 -␦, -␤, and -␥ (22). Only ␣ 1 1.2, and none of the auxiliary subunits, is required for the PKA-mediated increase in channel activity (23). ␣ 1 1.2 is phosphorylated in intact hippocampal neurons by PKA (24). The main phosphorylation site on ␣ 1 1.2 is serine 1928 (25, 26), which is important for the up-regulation of the channel activity by PKA (27). This site is close to the C terminus of ␣ 1 1.2, is present only in the full-length form of ␣ 1 1.2 (21), and is removed by the Ca 2ϩ -activated protease calpain after Ca 2ϩ influx through NMDA receptors (28). Calpain cleaves ␣ 1 1.2 Ϸ300 residues upstream of the C terminus in vitro (28). Deletion of the last 300-400 residues of ␣ 1 1.2 increases channel activity when expressed in Xenopus oocytes (29); therefore, calpain-mediated cleavage may permanently elevate Ca v 1.2 activity in vivo. Because calpain has been impli...

Differential Effects of Corticosterone on the Slow Afterhyperpolarization in the Basolateral Amygdala and CA1 Region: Possible Role of Calcium Channel Subunits

“…For incorporation of I CaL-1.2 and I CaL-1.3 we relied on the present in situ hybridization observations. At the single-cell level, mRNA expression levels for these subunits were indeed found to correlate quite well with the current amplitude (Chen et al 2000), although we certainly cannot exclude that posttranslational modification of channel subunits also plays a role in their functional relevance (see, e.g., Davare and Hell 2003). In the CA1 model, I CaL-1.2 was fivefold more abundant than I CaL-1.3 , supported also by data showing that the L-type calcium current of CA1 neurons is reduced to Ͻ20% in Cav1.2 knockout mice (Moosmang et al 2005).…”

“…For instance, the increased sAHP amplitude seen with aging is thought to develop secondary to enhanced calcium influx through L-type channels (Markaki et al 2005;Power et al 2002;Thibault et al 2007). This involves enhanced levels of the Cav1.3 subunit (Herman et al 1998;Veng et al 2003), much more so than of the Cav1.2 subunit (Davare and Hell 2003;Herman et al 1998), although posttranslational modification of Cav1.2 may also play a role (Davare and Hell 2003). Corticosterone has been reported to strongly increase high-voltage-activated sustained calcium currents in CA1 neurons (Karst 1994(Karst , 2000Kerr 1992), by doubling the number of functional L-type channels in the plasma membrane (Chameau et al 2007).…”

Lack of serotonin1B receptor expression leads to age-related motor dysfunction, early onset of brain molecular aging and reduced longevity

“…Aging leads to morphological [1][2][3][4][5] and functional [6][7][8][9] changes in the brain and is associated with increased risk for psychiatric and neurological disorders. [10][11][12][13] However, the mechanisms underlying normal aging of the brain likely differ from those associated with neurodegenerative and pathological conditions and are still poorly understood.…”

Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca2+/Calmodulin Promotes CaMKII Binding

“…Basically, doubling of the exposure time has to lead to a doubling of the signal as we published earlier (41,42). Signals were scanned using an Epson Perfection 4180 Photo flatbed scanner and EPSONscan software (42).…”