Abstract
The effects of stresscopin (SCP) on rat paraventricular nucleus (PVN) neurons were examined using whole-cell patch-clamp recordings and single-cell reverse-transcription multiplex polymerase chain reaction (SC-RT-mPCR) techniques. Under current-clamp conditions, bath application of SCP (100 nM) induced inhibition in 35.2% (37/105) of putative magnocellular neurons and 24.7% (20/81) of putative parvocellular neurons, and excitation in 5.7% (6/105) of putative magnocellular neurons and 18.5% (15/81) of putative parvocellular neurons. SCP-induced inhibition persisted in the presence of a mixture of TTX, a voltage-gated Na+ channel blocker, CNQX, an AMPA/kainate receptor antagonist and bicuculline, a GABAA receptor antagonist, whereas SCP-induced excitation of PVN neurons was reversed by the mixture. The SCP-induced inhibition of PVN neurons was abolished by bath application of antisauvagine-30, a selective CRF receptor 2 (CRF-R2) antagonist. Under voltage-clamp conditions, SCP evoked outward currents at the holding potential (−60 mV), which reversed near the potassium equilibrium potential. The SCP-evoked membrane currents were completely blocked by bath application of tertiapin-Q, a selective blocker of G protein-activated inwardly rectifying potassium (GIRK) channels. SC-RT-mPCR analysis indicated that all the SCP-sensitive PVN neurons (57 SCP-inhibited neurons, 21 SCP-excited neurons) expressed CRF-R1 and CRF-R2 mRNAs. Among SCP-hyperpolarized PVN neurons, oxytocin (OT) mRNA was detected in 91.8% of putative magnocellular neurons and 45.0% of putative parvocellular neurons. OT mRNA was also detected in 26.6% of SCP-depolarized parvocellular neurons, but not in SCP-depolarized magnocellular neurons. These results indicate that SCP inhibits a subpopulation of PVN neurons, especially OTergic magnocellular neurons, by enhancing the activity of GIRK channels via CRF-R2.
Highlights
Corticotropin-releasing factor (CRF), a 41-amino acid peptide, is synthesized and secreted in many regions of the central nervous system, and plays a key role in the coordination of endocrine and behavioral responses to stress
These results indicate that the SCP-elicited excitation of a subpopulation of paraventricular nucleus (PVN) neurons was likely achieved indirectly through a circuitry effect
We found that bath application of SCP induced inhibition in 35.2% of putative magnocellular neurons and 24.7% of putative parvocellular neurons, and excitation in 5.7% of putative magnocellular neurons and 18.5% of putative parvocellular neurons
Summary
Corticotropin-releasing factor (CRF), a 41-amino acid peptide, is synthesized and secreted in many regions of the central nervous system, and plays a key role in the coordination of endocrine and behavioral responses to stress. Human urocortin III, known as stresscopin (SCP), is a 38-amino acid peptide of the CRF family [1,2]. SCP is presumed to be a specific ligand for CRF-R2, and binds and activates the receptor [1,3,4]. In vitro binding studies have shown that SCP binds CRF-R2 with high affinity but has minimal affinity for CRF-R1, and it stimulates cAMP production in cells expressing CRF-R2, but not in cells expressing CRF-R1 [1,2]. CRF binds with high affinity to CRF-R1 [5]. CRF-R2 (a) is expressed mainly in the hypothalamic ventromedial nucleus and paraventricular nucleus (PVN), medial amygdaloid nucleus and lateral septic nucleus of the brain [7], and both CRF-R1 mRNA and CRF-R2 mRNA are expressed in putative parvocellular neurons in the PVN of rats [8]
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