Intracellular Calcium Concentrations Regulated by Cyclic ADP-Ribose and Heat in the Mouse Hypothalamus

Abstract

Oxytocin (OT) is synthesized and released in the hypothalamus, and plays a critical role in social recognition and behavior in mammals. Brain OT release is largely due to elevation of intracellular cytosolic calcium concentrations ([Ca 2+ ] i ) induced by mobilization of Ca 2+ from Ca 2+ pools by cyclic ADP-ribose (cADPR) catalyzed by the ADPribosyl cyclase activity of CD38. Recently, we reported that extracellular application of cADPR, together with heat, increased [Ca 2+ ] i in cultured neuronal tumor cells. Here, we examined whether this co-activation mechanism on [Ca 2+ ] i by cADPR and heat occurs in intact hypothalamic neurons of mice. Extracellular application of cADPR to cultured hypothalamic cells dissected from the anterior hypothalamus of male ICR mice elevated [Ca 2+ ] i at 35 C, and the [Ca 2+ ] i elevation was significantly enhanced at much higher temperatures up to 39 C. This [Ca 2+ ] i increase was mimicked differentially by ADPR and -NAD + , but blocked by cADPR antagonists, 8-Bromo-cADPR and ryanodine, or 2-aminoethoxydiphenyl borate, a TRPM2 channel antagonist. The [Ca 2+ ] i elevation was enhanced by cADPR and high temperature in neurons dissociated from the supraoptic nucleus of the hypothalamus, in which application of OT also increased [Ca 2+ ] i . mRNA of TRPM2 cation channels were expressed in the mouse hypothalamus of the ICR strain and humans. These results suggest that both cADPR-dependent Ca 2+ mobilization and heat-sensitive TRPM2-dependent cation influx contribute to the [Ca 2+ ] i elevation in hypothalamic neurons, which may contribute to OT secretion in the hypothalamus.

The Roles of Oxytocin and CD38 in Social or Parental Behaviors

“…Other types of voltage-dependent Ca 2+ channels are also involved in oxytocinergic neurons (Tobin et al, 2011). Recently, we showed that OXT release is also sensitive to hyperthermia and Ca 2+ influx via TRPM2 channels (Amina et al, 2010; Liu et al, 2012a). …”

Acetylcholine-Induced M/KCNQ Current Inhibition is Regulated by CD38 and A-Kinase Anchoring Protein in Neuroblastoma Cells

“…We cannot exclude the possibility that CD38 may act as a binding partner of M-channels or other types of ion channels, because it has recently been shown that CD38 and TRPM2 are co-immunoprecipitated and functionally interact and that CD38 acts as an activating element for hypertonicity-induced cation channels and TRPM2 channels in cell proliferation or hypertonic volume response of cells (Numata et al, 2012). We also showed that TRPM2 channels are involved in cADPR-induced [Ca 2+ i increases in NG108-15 cells , which may explain hyperthermia-induced [Ca 2+ i increases in the hypothalamus (Liu et al, 2012). Therefore, it is of interest to examine whether TRPM2 also contributes to mAChR signaling.…”

Somato-axodendritic release of oxytocin into the brain due to calcium amplification is essential for social memory

“…Subsequently, in isolated hypothalamic neurons, application of 100 pM OT results in [Ca 2+ ] i increases: a rapid initial increase and a sustained elevation lasting for 5 min [ 69 ]. OT elicits an initial elevation of the maximum [Ca 2+ ] i , and this phase is IP 3 -dependent.…”

“…Pretreatment with 8-bromo-cADPR, an antagonist of the cADPR-binding site of Ca 2+ release channels of ryanodine, inhibits OT-mediated sustained [Ca 2+ ] i increases. ADPR and β-NAD + also induce elevation of [Ca 2+ ] i and replicate the second phase of sustained [Ca 2+ ] i increases [ 49 , 69 ]. Under Ca 2+ -free conditions, the OT-mediated increase of [Ca 2+ ] i shows little change in either phase, suggesting that the two phases of [Ca 2+ ] i elevation in hypothalamic neurons are due to Ca 2+ mobilization from the intracellular Ca 2+ pools [ 49 ].…”