Calcium release into the cytosol via the inositol 1,4,5-trisphosphate receptor (IP₃R) calcium channel is important for a variety of cellular processes. As a result, impairment or inhibition of this release can result in disease. Recently, mutations in all four domains of the IP₃R have been suggested to cause diseases such as ataxia, cancer, and anhidrosis; however, most of these mutations have not been functionally characterized. In this review we summarize the reported mutations, as well as the associated symptoms. Additionally, we use clues from transgenic animals, receptor stoichiometry, and domain location of mutations to speculate on the effects of individual mutations on receptor structure and function and the overall mechanism of disease.

Ca²⁺ is a ubiquitous and versatile second messenger, which is important for processes like cell death and survival. Intracellular Ca²⁺ dynamics are tightly controlled by several Ca²⁺-transport systems. The main intracellular Ca²⁺-release channel is inositol 1,4,5-trisphosphate (IP₃) receptor (IP₃R), which is responsible for the Ca²⁺ flux from the endoplasmic reticulum. IP₃R dysfunction has been implicated in various pathological conditions including cancer and neurodegenerative diseases. Hence, IP₃Rs function at the common cross-point of different pro-survival and cell-death signaling pathways and are targeted by several proteins. A number of protein modifications directly impact IP₃R gating and thus Ca²⁺-flux properties. Yet, several regulating mechanisms emerged to regulate total IP₃R levels by altering IP₃R stability and turnover through proteasomal degradation and protease cleavage. In the present review, we will highlight the mechanisms and the impact of (i) IP₃R ubiquitination and the following proteasomal degradation and (ii) IP₃R cleavage by two major classes of proteases, namely caspases and calpains.

Mammalian cells express three highly conserved inositol 1,4,5-trisphosphate (IP₃) receptor types (IP₃R1, IP₃R2 and IP₃R3), which have broadly similar characteristics, but markedly different distributions, and form homo- or heterotetrameric Ca²⁺ channels in endoplasmic reticulum (ER) membranes. A vast array of published work details how mature, ER membrane-located IP₃ receptor tetramers are regulated, but much less attention has been paid to the intriguing questions of how the tetramers are assembled and destroyed as part of their natural life cycle. Are they assembled at the ER membrane from nascent, or completely translated polypeptides? How are they disassembled and degraded? These questions and other recently defined modes of IP₃ receptor processing will be briefly reviewed.

Mammalian parents participate in infant care. We previously demonstrated that sires of a strain of non-monogamous laboratory mice initiate parental retrieval behavior in response to olfactory and auditory signals from the dam during isolation in a new environment. This behavior is rapidly lost in the absence of such signals when the sires are caged alone. The neurocircuit and hormones that control such paternal behavior are not wellunderstood. CD38, a membrane glycoprotein, catalyzes synthesis of cyclic ADP-ribose and facilitates oxytocin (OT) secretion in oxytocinergic neurons in the hypothalamus, because formed cyclic ADP-ribose increases in cytosolic free calcium concentrations. Here, we studied CD38 in the nucleus accumbens (NAcc) on paternal pup retrieval behavior using CD38 knockout (CD38^–/–) mice of the ICR strain. CD38^–/– sires failed to retrieve when they were reunited with their pups after isolation together with the mate dams, but not with pup, in a novel cage for 10 min. When human CD38 was introduced in the NAcc of CD38^–/– sires using a lentiviral infection technique, the sires expressing CD38 in the NAcc showed retrieval behavior. Complete recovery of retrieval was obtained in sires with the expression of CD38 in the NAcc in combination with OT administration.

Oxytocin (OT) is a critical molecule for social recognition that mediates social and emotional behaviors. OT is released during stress and acts as an anxiolytic factor. Recently, the precise molecular mechanisms underlying OT release into the brain during stress are resolved. We examined that OT brain release in male mice is regulated by cyclic ADP-ribose (cADPR) and heat (fever) in vitro and in vivo under stress conditions. Significantly higher levels of OT release were observed in the hypothalamus culture isolated from subordinate mice in group-housed males than ordinate mice after cage-switch stress. OT concentrations in micro-perfusates at the paraventricular nucleus upon perfusion stimulation with cADPR were enhanced in subordinate mice compared to ordinate mice. The OT concentration in the cerebrospinal fluid (CSF) was higher in endotoxin-shock mice with fever than in controls with no body temperature increase. In mice exposed to the new environmental stress, the CSF OT level transiently increased at 5 minutes from start, while the rectal temperature increased. OT release under various conditions was sensitive to antagonists, gene knockout or mRNA levels of CD38 or TRPM2. These results indicate that cADPR and hyperthermia co-regulate hypothalamic OT secretion during social stress by elevation of intracellular free Ca²⁺ concentrations involved in CD38-dependent Ca²⁺ mobilization and TRPM2-dependent Ca²⁺ influx. Interaction between CD38 and TRPM2 seems to be a new mechanism for stress-induced release of OT that may result in anxiolytic effects and remission of autistic phenotypes.

Recent studies show that seminal NADase is part of the CD38 family and has multiple roles in reproductive biology, especially in male infertility: CD38 in seminal plasma plays a critical role in regulating maternal immune function as well as sperm motility and acrosome reactions through Ca²⁺ signaling. In this short review, I summarize the structure and source of seminal CD38 as well as its effects on reproductive function.

CD157, known as bone marrow stromal cell antigen-1, is a glycosylphosphatidylinositol-anchored ADP-ribosyl cyclase supporting survival and function of B lymphocytes and hematopoietic or intestinal stem cells. It was first reported in 2009 that CD157 is a risk locus in Parkinson's disease. To analyze the role of CD157 in the nervous system and how this molecule contributes to Parkinson's disease progression, we used CD157 knockout (KO) mice. CD157 KO mice show no coordinate motor dysfunction, but very low daily activity. CD157 KO adult male mice exhibited anxiety-related behavior, social avoidance, severe fear and depression-like behavior, compared with wild-type mice. This depression-like behavior was rescued by three types of anti-depressants. These results demonstrate a critical role for CD157 in neuropsychiatric functions, which makes it a potential new target for psychiatric symptoms.

CD38 produces Ca²⁺-mobilizing second messengers, cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate, at its catalytic site. The molecular mechanism of enzymatic activation modulation has not been completely elucidated. We hypothesized that the β isoform of Ca²⁺-calmodulin-dependent protein kinase II (CaMKII) has a modulator activity on CD38. Functional interaction between CD38 and CAMKIIβ was studied, focusing on cell migration and Ca²⁺ signaling in wound-healing assay. The healing border showed irregular characteristics, with protrusions in HA-CD38 cDNA-transfected samples, and CD38-expressed cells were localized at the tip, likely to behave as 'leader cells,' and at the bottom and edge of protrusions. However, HA-CD38 cDNA-transfected samples treated with a CaMKII inhibitor, KN-62, showed a rather smooth front with less migration during the healing process, and CD38-expressed cells were diffusely localized. Such healing phenomena were not apparent in mock-transfected HEK cells. These results indicate that CD38-dependent cell migratory characteristics are modulated by CaMKII.

IP₃ receptors act as Ca²⁺ channels to control vital phenomena and disorders, but the fundamental mechanism of how IP₃ opens the channel remains elusive. The recent advances in cryo-electron microscopy has enabled the construction of a near atomic model of the tetrameric IP₃ receptor. The most recent X-ray crystallography demonstrated that binding of IP₃ resulted in global allosteric conformational changes of the large cytosolic domain. Further, functional analyses revealed that a unique leaflet structure transmits the conformational changes to the channel upon activation of IP₃ receptors by IP₃. In this review, we outline recent evidence for the gating mechanism of the IP₃ receptor, and discuss remaining unsolved issues.