Immunohistochemical localization of HCA1 receptor in placenta in presence of fetal growth restriction.

INTRODUCTION: Glucose metabolism produces lactate and hydrogen ions in an anaerobic environment. Fetuses with intrauterine growth restriction are considered to become progressively lactacidemic as well as hypoxic. Roles of lactate in the placenta in the presence of fetal growth restriction (FGR) remain to be clarified. METHODS: Immunohistochemical localization of lactate-related substances, such as a receptor for lactate (hydroxy-carboxylic acid 1 receptor (HCA1 receptor/GPR81)), monocarboxylate transporters (MCTs) for lactate, lactate dehydrogenases (LDHs), and proteins expressed in syncytiotrophoblasts or cytotrophoblasts was examined in placentas of appropriate weight for gestational age (AGA) fetus and those showing FGR. RESULTS: Immunoreactivity for the HCA1 receptor was present in the cytoplasm of some trophoblasts, predominantly localized to their basal (fetus-facing) side, and was frequently colocalized with that for E-cadherin or serine peptidase inhibitor, Kunitz type 1 (SPINT1), a marker protein of cytotrophoblasts. Immunoreactivity for MCT1 and MCT4 was present on the basal and the microvillous (maternal-facing) membranes of trophoblasts in both groups, respectively. Clear immunoreactivity for LDHA and LDHB was also observed in the cytoplasm of trophoblasts, mainly localized to their basal side. However, there were no significant differences in immunohistochemically stained areas of lactate-related substances between AGA and late-onset FGR groups. On the other hand, there were correlations between coefficients of the presence of chorioamnionitis and the values of LDHB and E-cadherin. DISCUSSION: Immunohistochemical localization of the HCA1 receptor was predominantly observed in the cytoplasm located on the basal side of trophoblasts, suggesting a role of lactate in human placental development, including syncytialization.

Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue.

Lactate can be used by neurons as an energy substrate to support their activity. Evidence suggests that lactate also acts on a metabotropic receptor called HCAR1, first described in the adipose tissue. Whether HCAR1 also modulates neuronal circuits remains unclear. In this study, using qRT-PCR, we show that HCAR1 is present in the human brain of epileptic patients who underwent resective surgery. In brain slices from these patients, pharmacological HCAR1 activation using a non-metabolized agonist decreased the frequency of both spontaneous neuronal Ca2+ spiking and excitatory post-synaptic currents (sEPSCs). In mouse brains, we found HCAR1 expression in different regions using a fluorescent reporter mouse line and in situ hybridization. In the dentate gyrus, HCAR1 is mainly present in mossy cells, key players in the hippocampal excitatory circuitry and known to be involved in temporal lobe epilepsy. By using whole-cell patch clamp recordings in mouse and rat slices, we found that HCAR1 activation causes a decrease in excitability, sEPSCs, and miniature EPSCs frequency of granule cells, the main output of mossy cells. Overall, we propose that lactate can be considered a neuromodulator decreasing synaptic activity in human and rodent brains, which makes HCAR1 an attractive target for the treatment of epilepsy.

Immunoreactivity of receptor and transporters for lactate located in astrocytes and epithelial cells of choroid plexus of human brain.

Glucose metabolism produces lactate and hydrogen ions in an anaerobic environment. Cerebral ischemia or hypoxia is believed to become progressively lactacidemic. Monocarboxylate transporters (MCTs) in endothelial cells are essential for the transport of lactate from the blood into the brain. In addition, it is considered that MCTs located in astrocytic and neuronal cells play a key role in the shuttling of energy metabolites between neurons and astrocytes. However, roles of lactate in the brain remain to be clarified. In this study, the localization of lactate transporters and a receptor for cellular uptake of lactate was immunohistochemically examined in autopsied human brains. Immunoreactivity for MCT1 was observed in the apical cytoplasmic membrane of some epithelial cells in the choroid plexus as well as astrocytes and the capillary wall, whereas that for MCT4 was found in the basolateral cytoplasmic membrane of small number of epithelial cells as well as astrocytes and the capillary wall. In addition, immunoreactivity for the hydroxy-carboxylic acid 1 receptor (HCA1 receptor), a receptor for cellular uptake of lactate, was also found on the basolateral cytoplasmic membrane of epithelial cells as well as astrocytic and neuronal cells. Immunoreactivity for lactate dehydrogenase (LDH)-B was observed in the cytoplasm of epithelial cells in the choroid plexus as well as astrocytes and the capillary wall. These immunohistochemical findings indicate the localization of MCT1, MCT4, the HCA1 receptor, and LDH-B in epithelial cells of the choroid plexus as well as astrocytes, and suggest the transport of intravascular lactate into the brain through epithelial cells of the choroid plexus as well as cerebral vessels and the possibility of lactate being utilized in epithelial cells.

Modulation of hippocampal excitability via the hydroxycarboxylic acid receptor 1.

In addition to its prominent role as an energetic substrate in the brain, lactate is emerging as a signaling molecule capable of controlling neuronal excitability. The finding that the lactate-activated receptor (hydroxycarboxylic acid receptor 1; HCA1) is widely expressed in the brain opened up the possibility that lactate exerts modulation of neuronal activity via a transmembranal receptor-linked mechanism. Here, we show that lactate causes biphasic modulation of the intrinsic excitability of CA1 pyramidal cells. In the low millimolar range, lactate or the HCA1 agonist 3,5-DHBA reduced the input resistance and membrane time constant. In addition, activation of HCA1 significantly blocked the fast inactivating sodium current and increased the delay from inactivation to a conducting state of the sodium channel. As the observed actions occurred in the presence of 4-CIN, a blocker of the neuronal monocarboxylate transporter, the possibility that lactate acted via neuronal metabolism is unlikely. Consistently, modulation of the intrinsic excitability was abolished when CA1 pyramidal cells were dialyzed with pertussis toxin, indicating the dependency of a Gαi/o -protein-coupled receptor. The activation of HCA1 appears to serve as a restraining mechanism during enhanced network activity and may function as a negative feedback for the astrocytic production of lactate.