Gastrin‐releasing peptide acts via postsynaptic BB₂ receptors to modulate inward rectifier K⁺ and TRPV1‐like conductances in rat paraventricular thalamic neurons

Abstract

Key points• Gastrin-releasing peptide (GRP) is a mammalian bombesin-like peptide that is widely distributed in the CNS. Whereas GRP is known to have a predominant excitatory action on neurons, details of the underlying membrane mechanism remain largely undefined.• We investigated GRP-affected receptors and ionic conductances in the midline paraventricular thalamic nucleus, a brain region densely innervated by GRP-like immunoreactive fibres.• Perforated patch clamp recording in acute brain slices showed that exposure of paraventricular thalamic nucleus neurons to low nanomolar concentrations of GRP resulted in membrane depolarization with rhythmic burst or tonic firing. These responses were due to a postsynaptic bombesin type 2 receptor-mediated simultaneous suppression of a Ba 2+ -sensitive inward rectifier K + conductance and activation of a non-selective cation conductance with transient receptor potential vanilloid 1-like properties.• The data provide details on the nature of the receptor and ionic conductances involved in GRP's excitatory influence on midline thalamic neurons.Abstract Gastrin-releasing peptide (GRP) is a bombesin-like peptide with a widespread distribution in mammalian CNS, where it has a role in food intake, circadian rhythm generation, fear memory, itch sensation and sexual behaviour. While it has been established that GRP predominantly excites neurons, details of the membrane mechanism involved in this action remain largely undefined. We used perforated patch clamp recording in acute brain slice preparations to investigate GRP-affected receptors and ionic conductances in neurons of the rat paraventricular thalamic nucleus (PVT). PVT is a component of the midline and intralaminar thalamus that participates in arousal, motivational drives and stress responses, and exhibits a prominence of GRP-like immunoreactive fibres. Exposure of PVT neurons to low nanomolar concentrations of GRP induced sustained TTX-resistant membrane depolarizations that could trigger rhythmic burst discharges or tonic firing. Membrane current analyses in voltage clamp revealed an underlying postsynaptic bombesin type 2 receptor-mediated inward current that resulted from the simultaneous suppression of a Ba 2+ -sensitive inward rectifier K + conductance and activation of a non-selective cation conductance with biophysical and pharmacological properties reminiscent of transient receptor potential vanilloid (TRPV) 1. A role for a TRPV1-like conductance was further implied by a significant suppressant influence of a TRPV1 antagonist on GRP-induced membrane depolarization and rhythmic burst or tonic firing. The results provide a detailed picture of the receptor and ionic conductances that are involved in GRP's excitatory action in midline thalamus.

Limbic thalamus and state-dependent behavior: The paraventricular nucleus of the thalamic midline as a node in circadian timing and sleep/wake-regulatory networks

“…These contain, for example, Leu-enkephalin (Battaglia et al, 1992;Uroz et al, 2004); endomorphin (Pierce and Wessendorf, 2000); somatostatin (Molinari et al, 1987); substance P (Battaglia et al, 1992;Molinari et al, 1987;Uroz et al, 2004), deriving in the rat from the brain stem (Otake, 2005); cholecystokinin (Battaglia et al, 1992;Molinari et al, 1987;Otake, 2005), deriving in the rat from the periaqueductal gray, dorsal raphe and dorsomedial nucleus of the hypothalamus (Otake, 2005); neuropeptide Y (Freedman and Cassell, 1994;Kampe et al, 2009;Molinari et al, 1987); corticotropin-releasing hormone (Hsu and Price, 2009); thyrotropin-releasing hormone (Merchenthaler et al, 1988;Wittmann et al, 2009); cocaine and amphetamine-related transcript (CART), which derive from hypothalamic cell groups including the dorsomedial nucleus (Kampe et al, 2009;Kirouac et al, 2006;Parsons et al, 2006); gastrin-releasing peptide (GRP) (Hermes et al, 2013), vasoactive intestinal polypeptide (VIP) and arginine-vasopressin (AVP), which derive from the SCN (Freedman and Cassell, 1994;Novak et al, 2000a; see Section 3.1). As mentioned above, fibers deriving from orexincontaining neurons have been added in recent years to the long list of peptidergic innervation of the thalamic midline (see Section 3.5).…”

Counter-stimuli Inhibit GRPR Neurons via GABAergic Signaling in the Spinal Cord

“…The suppression of an inward rectifier K + current and/or the activation of a non-selective cation conductance could contribute to the GRP-generated current ( Supplementary Fig. 5) (Hermes et al, 2013).…”

Insights into bombesin receptors and ligands: Highlighting recent advances

“…This is primarily accomplished through coupling to the Gq/11 and G12/13 families of heterotrimeric G-proteins [129,255,298]. BnR’s activation stimulate a number of other signaling cascades including activation of Phospholipase D and A2, small GTP binding proteins such as Rho, protein kinase D and various ion channels [111,129,326,354,397]. After activation BnR’s undergo a number of receptor modulatory processes including receptor phosphorylation [13,129,154,155,380], internalization and recycling [24–26,129,317,327,352,353,379], down-regulation [25–27,129,353] and desensitization [23,25–27,129].…”