P2‐084: T‐type voltage‐gated calcium channel activated by ST101 is a novel molecular target as cognitive enhancer

Abstract

We have developed a novel cognitive enhancer, ST101 (spiro[imidazo[1,2- a]pyridine-3,2-indan]-2(3 H)-one; previously coded as ZSET1446, Sonexa Therapeutics, Inc. San Diego, CA). We previously reported that ST101 improves the impairment in hippocampal long-term potentiation (LTP) via activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) in olfactory bulbectomized (OBX) mice (Han et al., 2008). As yet, the mechanisms underlying the activation of memory-related protein kinases are not known. Rat somatosensory cortical and hippocampal slices were incubated with 0.01 to 100 nM ST101 in the perfusion chamber with or without voltage-gated calcium channel (VGCC) inhibitors and performed immunoblotting and electrophysiological analyses. Treatment of the cortical slices with a range of ST101 concentrations significantly increased CaMKII autophosphorylation with a bell-shaped dose-response curve, with the maximal effective concentration at 0.1 nM ST101. The enhanced CaMKII autophosphorylation with 0.1 nM ST101 treatment was significantly inhibited by pretreatment with 1 m M mibefradil, a T-type VGCC inhibitor, but not with N-type (w -conotoxin), P/Q-type (w -agatoxin) or L-type (nifedipine) VGCC inhibitors. Similarly, 0.1 nM ST101 significantly potentiated LTP, which was inhibited by 1 m M mibefadil treatment in cortical slices. Finally, whole-cell patch-clamp analysis of Neuro2A cells overexpressing recombinant human Ca V 3.1 (a 1G) T-channels confirmed that T-type VGCC currents are stimulated with 0.1 nM ST101 (1). These results indicate that T-type VGCCs are direct molecular targets for the novel cognitive enhancer ST101, a potential Alzheimer disease therapeutics.(1) Moriguchi et al. Journal of Neurochemistry (2012) The T-type voltage-gated calcium channel as a molecular target of the novel cognitive enhancer ST101: Enhancement of long-term potentiation and CaMKII autophosphorylation in rat cortical slices.(doi: 10.1111/j.1471-4159.2012.07667.x.)