Insulin-Like Growth Factor-1 Modulation of CaV1.3 Calcium Channels Depends on Ca2+ Release from IP3-Sensitive Stores and Calcium/Calmodulin Kinase II Phosphorylation of the  1 Subunit EF Hand

Abstract

In neurons, L-type calcium channels (CaV1.2 and CaV1.3) regulate an extensive range of functions. However, the roles of CaV1.3-containing L channels, which are physiologically and pharmacologically distinct from the better understood CaV1.2 channels, are only beginning to be determined. We find that CaV1.3 channels are modulated by the insulin-like growth factor-1/receptor tyrosine kinase (IGF-1/RTK) through a signaling pathway that involves phospholipase C, calcium release from IP 3 -sensitive internal stores, and calcium/ calmodulin kinase II. In addition, we find that the IGF-1-induced modulation requires phosphorylation of a specific serine residue, S1486, in the EF hand motif of the CaV1.3 subunit. This modulation alters CaV1.3 activity, causing a left shift in the current-voltage relationship and strongly potentiating peak currents at hyperpolarized membrane potentials. We also find that CaV1.3 channels and their RTKdependent potentiation contribute to the regulation of the survival-promoting transcription factor cAMP response element-binding protein (CREB): in both cortical and hippocampal neurons, depolarization and IGF-1 rapidly increase phospho-CREB levels in a manner that requires CaV1.3 activity and the S1486 phosphorylation site to achieve a full effect. Although the full effects of CaV1.3 channels remain to be determined, their preferential localization to dendritic shafts and spine heads coupled with their ability to activate at relatively hyperpolarized and even subthreshold potentials suggests that CaV1.3 activity may subserve different cellular functions from CaV1.2 and, in particular, may be important in transducing signals initiated by excitatory neurotransmission.

Erbin Enhances Voltage-Dependent Facilitation of Cav1.3 Ca2+Channels through Relief of an Autoinhibitory Domain in the Cav1.3 α1Subunit

“…Although PKA and CaMKII also cause facilitation of Ca v 1.3 channels (Qu et al, 2005;Gao et al, 2006), the enhanced facilitation caused by erbin and splice variation of the ␣ 1 1.3 CT in our study differs from these mechanisms in a number of ways. First, although PKA and CaMKII cause an increase in Ca v 1.3 peak current amplitude (Qu et al, 2005) and negative shift in voltagedependent activation (Gao et al, 2006), respectively, erbin had neither effect on Ca v 1.3 activation in our study (Fig. 4).…”

“…4). Second, CaMKII activation by insulin-like growth factor causes facilitation of both Ca v 1.3 and Ca v 1.3b (Gao et al, 2006), whereas we find that Ca v 1.3 but not Ca v 1.3b channels are subject to erbindependent facilitation (Figs. 5, 8).…”

“…For Ca v 1.2 L-type channels, various mechanisms for facilitation have been characterized, including those involving phosphorylation of the channel by cAMP-dependent protein kinase (PKA) (Catterall, 2000) and association with calmodulin-dependent protein kinase II (CaMKII) (Dzhura et al, 2000;Hudmon et al, 2005;Grueter et al, 2006;Lee et al, 2006). Although PKA and CaMKII also cause facilitation of Ca v 1.3 channels (Qu et al, 2005;Gao et al, 2006), the enhanced facilitation caused by erbin and splice variation of the ␣ 1 1.3 CT in our study differs from these mechanisms in a number of ways. First, although PKA and CaMKII cause an increase in Ca v 1.3 peak current amplitude (Qu et al, 2005) and negative shift in voltagedependent activation (Gao et al, 2006), respectively, erbin had neither effect on Ca v 1.3 activation in our study (Fig.…”

α1-Adrenergic Receptor-Induced Heterosynaptic Long-Term Depression in the Bed Nucleus of the Stria Terminalis Is Disrupted in Mouse Models of Affective Disorders

“…L-type VGCC activity (particularly Ca V1.3 ) is required in the dorsal striatum to induce corticostriatal group I mGluR-LTD (Wang et al, 2006). Furthermore, it has recently been demonstrated in the hippocampus that signaling via phospholipase C can increase the conductance of Ca V1.3 at negative potentials (Gao et al, 2006). Consistent with the role of the L-type VGCC in the induction of group 1 mGluR-LTD in the dorsal striatum, postsynaptic cells must be depolarized to À50 mV (Adermark and Lovinger, 2007).…”

Does Increased IGF-1 Concentration Have a Clear Positive Significance in Reducing Depression and Posttraumatic Arousal Symptoms?

“…All we know is that a decreased level of insulin-like growth factor may promote development of cognitive dysfunction, 3 and that IGF-1 is involved in regulating hippocampal neurogenesis, forming abnormal neural network, and affecting the excitability of hippocampal neurons. 4 Dr. Rusch's paper tends to make readers believe that the increase of IGF-1 has an effect on the improvement of patients' cognitive function; however this remains unknown and requires verifi cation by further research. …”