Neurobiological role of secretin and its receptor in osmoregulation

Abstract

Osmoregulation is a survival key for terrestrial animals to defend constant osmotic risks from surroundings. Water imbalance would lead to irreversible damages to major organs, thus a sophisticated physiological and behavioural responses are evolved so as to maintain the constancy of milieu interieur. Recently, Secretin (SCT) has been shown as a neurophysiological factor in osmoregulation. Our previous studies revealed that SCT and its receptor (SCTR) can control water drinking behaviour and vasopressin (Vp) release during dehydration. Moreover, SCT/SCTR axis is required to mediate angiotensin II (ANGII) osmoregulatory actions and, SCTR and angiotensin II receptor type 1 subtype a (AT1aR) are able to form heteromer and regulate hyperosmolality-induced water drinking behaviour. Among the network of central osmoregulatory sites, subfornical organ (SFO) is the most upstream regulator with excitatory and inhibitory efferent to other osmoregulatory brain sites and responsible in detecting and responding to osmolality changes. We have previously shown that SCT and ANGII are capable of stimulating SFO and water intake, however the detailed mechanism of how SCT/SCTR regulates water homeostasis within brain regions and its interaction with AT1aR in Vp release are still unclear.

Due to substantial data showing the close association between SCT and SFO in controlling water drinking, this study firstly investigated if SCT has a specific osmoregulatory action in SFO neurons by using mouse models with SCT or SCTR gene ablation in a SFO cell-specific manner. Under water depletion, SCTSFO-/- and SCTRSFO-/- mice remarkably suppressed water drinking and the differences between water and salt intakes were absent compared with the sham controls. Meanwhile cFos expression and transcript levels in SFO of these specific knockout mice were greatly reduced compared with control, indicating that loss of SCT/SCTR in SFO could suppress neuronal activation in SFO under dehydration, and therefore resulting in reduced water drinking. In line with the electrophysiological data about SCT’s actions on SFO neuron subtypes, it can be concluded that SCT majorly acts on SFO excitatory neurons to promote water intake during dehydration.

Next, the hypothesis that SCTR/AT1aR heteromer mediates Vp release within hypothalamus was extensively examined. Earlier studies have indicated that SCTR/AT1aR heteromer participates in hyperosmolality-induced water intake, yet no information is available concerning the potential interactions of SCTR with AT1aR to control Vp expression and release. In this study, transmembrane (TM) peptides were utilized as biochemical tools to dissect the in vivo actions of SCTR/AT1aR heteromer in paraventricular nucleus (PVN). Central injection of STM2 and ATM4 attenuated SCT/ANGII-induced plasma Vp release and expression in PVN, and central injection of STM2, but not mutant peptides, could also suppress SCT-induced cFos expression in mainly magnocellular PVN cells. Since Vp is produced in magnocellular neurons of PVN, therefore these results indicated that SCTR/AT1aR regulates Vp release and expression in PVN. Furthermore, SCT-induced PKA gene expression in PVN and SCT-induced phosphorylation of pCREB in PVN tissues were reduced when SCTR/AT1aR heteromers were disrupted. Consequently, these results revealed that SCTR/AT1aR heteromer regulates Vp expression and release via cFos/PKA/CREB in magnocellular PVN cells.