Rapid Central Corticosteroid Effects: Evidence for Membrane Glucocorticoid Receptors in the Brain1

Integrative and Comparative Biology, Sep 2005 by Tasker, Jeffrey G, Di, Shi, Malcher-Lopes, Renato

Studies of corticosteroid effects in vitro have demonstrated rapid modulation of voltage-gated Ca^sup 2 ^ currents in neurons mediated by G protein- and protein kinase-dependent mechanisms. Thus whole-cell patch clamp recordings in dissociated hippocampal CAl neurons revealed a rapid inhibitory effect of corticosterone on L- and N-type Ca^sup 2 ^ currents (ffrench-Mullen, 1995). This effect was suppressed by pertussis toxin and by intracellular blockade of G protein signaling and protein kinase C, suggesting that it was dependent on the activation of a receptor coupled to G^sub i/o^ and the protein kinase C signaling pathway. A recent combined patch clamp and Ca^sup 2 ^ imaging study of neurons dissociated from dorsal root ganglia showed a similar rapid inhibition of voltage-gated Ca^sup 2 ^ currents by corticosterone (He et al., 2003). This effect of corticosterone was also blocked by pertussis toxin pretreatment and by inhibitors of protein kinase C activity, suggesting that corticosteroids may have a generalized inhibitory effect on high voltage-activated Ca^sup 2 ^ currents that is dependent on the activation of a receptor coupled to G^sub i/o^ and protein kinase C.

RAPID GLUCOCORTICOID ACTIONS IN THE MAMMALIAN HYPOTHALAMUS

The inhibitory feedback effects of glucocorticoids on hypothalamic hormone secretion are both rapid, occurring and dissipating within minutes, and delayed, taking several minutes to hours and lasting for days. While the delayed glucocorticoid effects are widely held to involve canonical steroid regulation of gene transcription, the rapid effects are too fast to invoke transcriptional regulation and have long been thought to be caused by a non-genomic mechanism. Several in vivo and in vitro electrophysiological studies have been conducted in the hypothalamus, focusing primarily on the parvocellular neuroendocrine cells of the PVN, in an attempt to determine the mechanism of the fast glucocorticoid inhibition of the HPA axis.

Early in vivo extracellular recordings from PVN neurons projecting to the median eminence (i.e., putative parvocellular neuroendocrine cells) showed rapid responses to iontophoretic application of corticosteroids directly into the PVN (Kasai et al., 1988; Saphier and Feldman, 1988; Li et al., 1991). Although there was not complete consensus in these studies with respect to the valence of the corticosteroid response, both excitatory and inhibitory responses being reported, the predominant effect appeared to be an inhibition, consistent with a direct, rapid feedback inhibition of corticosteroids on the hypothalamic neurons involved in HPA activation.

Several in vitro studies have also shown rapid electrophysiological effects of corticosteroids on hypothalamic PVN neurons mediated by actions at putative membrane receptors. Although cortisol had little effect on the spiking activity of most neurons recorded extracellularly in the parvocellular region of the PVN in hypothalamic slices (Kasai and Yamashita, 1988a), it suppressed the excitatory effect of norepinephrine-induced activation of these neurons (Kasai and Yamashita, 1988b). This suggested that the rapid inhibitory effect of corticosteroids might be due to actions on presynaptic noradrenergic inputs to the PVN parvocellular neurons. However, another in vitro brain slice study suggested that glucocorticoids might have rapid effects on postsynaptic glutamate and GABA receptors in hypothalamic as well as celiac ganglion neurons, since responses to iontophoretically applied glutamate and GABA were attenuated and enhanced, respectively, by corticosteroids and this effect was not blocked by blocking synaptic transmission (Wang et al., 1996). Corticosteroids were also found to inhibit vasopressin release from brain slices through a non-genomic mechanism (Liu et al., 1995). These studies together, therefore, suggest that the inhibitory effects of corticosteroids on hypothalamic neuroendocrine function occur directly at the level of the PVN and involve a putative membrane glucocorticoid receptor. Corticosteroids appear to target synaptic activation of hypothalamic neurons since they have relatively little effect on resting membrane potential and basal firing rates, but attenuate the noradrenergic activation of the neurons and the modulation of glutamate and GABA responses (although direct cortisol effects on voltage-gated K channels have also been reported recently in PVN neurons in slices [Zaki and Barrett-Jolley, 2002]). It is interesting to note here that there is a strong presynaptic noradrenergic regulation of glutamate and GABA release onto PVN parvocellular (Daftary et al., 2000) and magnocellular neurons (Daftary et ai, 1998; Wang et al., 1998; Boudaba et al., 2003), and that corticosteroids may affect the activity of PVN neurons by modulating noradrenergic, glutamatergic and/or GABAergic synaptic inputs to these neurons.