Calmodulin-Binding Peptide PEP-19 Modulates Activation of Calmodulin Kinase IIIn Situ

Abstract

PEP-19 is a 6 kDa polypeptide that is highly expressed in select populations of neurons that sometimes demonstrate resistance to degeneration. These include the granule cells of the hippocampus and the Purkinje cells of the cerebellum. Its only identified activity to date is that of binding apo-calmodulin. As a consequence, it has been demonstrated to act as an inhibitor of calmodulin-dependent neuronal nitric oxide synthase in vitro, although PEP-19 regulation of calmodulin-dependent enzymes has never been characterized in intact cells. The activation of the calmodulin-dependent enzyme calmodulin kinase II (CaM kinase II) was studied in PC12 cells that had been transfected so as to express physiological levels of PEP-19. The expression of PEP-19 yielded a stable phenotype that failed to activate CaM kinase II upon depolarization in high K(+). However, CaM kinase II could be fully activated when calcium influx was achieved with ATP. The effect of PEP-19 on CaM kinase II activation was not attributable to changes in the cellular expression of calmodulin. The cellular permeability of the transfected cells to calcium ions also appeared essentially unchanged. The results of this study demonstrated that PEP-19 can regulate CaM kinase II in situ in a manner that was dependent on the stimulus used to mobilize calcium. The selective nature of the regulation by PEP-19 suggests that its function is not to globally suppress calmodulin activity but rather change the manner in which different stimuli can access this activity.

PCP4 regulates Purkinje cell excitability and cardiac rhythmicity

“…We identified marked enrichment of Pcp4 in the PC population ( Figure 1C). PCP4, also known as PEP-19, is a small IQ motif-containing protein of the calpacitin family of proteins and a negative regulator of calmodulin and Ca 2+ /calmodulindependent kinase II-dependent (CaMKII-dependent) signaling in neurons (15)(16)(17). Results were validated by reverse-transcription PCR (RT-PCR) ( Figure 1D) and quantitative PCR (qPCR) ( Figure 1E), which confirmed that Pcp4 was markedly enriched in PCs compared with VMs.…”

A Cytosolic STIM2 Preprotein Created by Signal Peptide Inefficiency Activates ORAI1 in a Store-independent Manner

“…Although the STIM2 SPF was unable to regulate basal Ca 2ϩ or SOCe, it nevertheless productively interacted with Ca 2ϩ /CaM and proved as efficient as STIM1 at stimulating the activity of NF-B-dependent gene transcription. Although the specific mechanisms underlying these effects are not yet clear, several SPFs and a number of endogenous peptides of a comparable size to the STIM2 SPF bind to Ca 2ϩ /CaM and act to inhibit a number of CaM-mediated processes (52)(53)(54)(55)(56). Conceivably, Ca 2ϩ /CaM may be required to facilitate SPF-mediated transcriptional activity as CaM acts via multiple mechanisms to regulate NF-B transcription, both positively (57,58) and negatively (58 -60).…”

Distinct ontogenic and regional expressions of newly identified Cajal-Retzius cell-specific genes during neocorticogenesis

“…The mutant of Cacna2d2 called ducky shows a reduction of a current density of VDCCs in Purkinje cells and impairs the dendritic formation of these cells (23). In addition, several intracellular calcium signaling molecules, including Dscr1l1, calretinin, Rit2, and Pcp4 (25)(26)(27), are selectively expressed in CR cells (Fig. 2 A).…”