Excitatory actions of peptide histidine isoleucine on thalamic relay neurons

Abstract

SummaryPeptide histidine isoleucine (PHI) and vasoactive intestinal peptide (VIP) are neuropeptides synthesized from a common precursor, prepro-VIP, and share structural similarity and biological functions in many systems. Within the central nervous system and peripheral tissues, PHI and VIP have overlapping distribution. PHI-mediated functions are generally via activation of VIP receptors; however, the potency and affinity of PHI for VIP receptors are significantly lower than VIP. In addition, several studies suggest distinct PHI receptors that are independent of VIP receptors. PHI receptors have been cloned and characterized in fish, but their existence in mammals is still unknown. This study focuses on the functional role of PHI in the thalamus because of the localization of both PHI and VIP receptors in this brain region.Using extracellular multiple-unit recording techniques, we found that PHI strongly attenuated the slow intrathalamic rhythmic activity. Using intracellular recording techniques, we found that PHI selectively depolarized thalamic relay neurons via an enhancement of the hyperpolarization-activated mixed cation current, I h . Further, the actions of PHI were occluded by VIP and dopamine, indicating these modulators converge onto a common mechanism. In contrast to previous work, we found that PHI was more potent than VIP in producing excitatory actions on thalamic neurons. We next used the transgenic mice lacking a specific VIP receptor, VPAC 2 , to identify its possible role in PHImediated actions in the thalamus. PHI depolarized all relay neurons tested from wild-type mice (VPAC 2 +/+ ); however, in knockout mice (VPAC 2 -/-), PHI produced no change in membrane potential in all neurons tested. Our findings indicate that excitatory actions of PHI are mediated by VPAC 2 receptors, not by its own PHI receptors and the excitatory actions of PHI clearly attenuates intrathalamic rhythmic activities, and likely influence information transfer through thalamocortical circuits.

The VPAC 2 agonist peptide histidine isoleucine (PHI) up‐regulates glutamate transport in the corpus callosum of a rat model of amyotrophic lateral sclerosis (hSOD1 G93A ) by inhibiting caspase‐3 mediated inactivation of GLT‐1a

“…However, such increase was barely detected in sample from paralyzed transgenic animals, suggesting that the disease was associated with an impaired expression of the corresponding neuropeptides. As the astrocytic VPAC1 and VPAC 2 receptors are known to mediate the biological actions of the VIP/PHI/PACAP neurotransmitters (27, 37), their expression profile was investigated in cultured astrocytes from the corpus callosum (Fig. 3 B , C ).…”

“…*P Ͻ 0.05, **P Ͻ 0.01, ***P Ͻ 0.001 vs. WT; ## P Ͻ 0.01, ### P Ͻ 0.001 vs. corresponding P60. and VPAC 2 receptors are known to mediate the biological actions of the VIP/PHI/PACAP neurotransmitters (27,37), their expression profile was investigated in cultured astrocytes from the corpus callosum ( Fig. 3B, C).…”

“…Herein, we provide evidence for a reduced GLT‐1‐dependent uptake and for changes in the expression of the C‐terminal splice variants in the corpus callosum of transgenic rats expressing a mutated form of human superoxide dismutase 1 (hSOD1 G93A ), raising the possibility of excitotoxic processes in this white matter structure at an early stage of ALS. Injection of PHI, a VPAC 2 agonist (27), into the corpus callosum resulted in a robust up‐regulation of GLT‐1 activity in animals showing ALS symptoms. Considering the putative role played by caspase‐3 in the regulation of GLT‐1 in ALS (28, 29), the involvement of this enzyme in the effects of PHI was further investigated in vivo and in cultured astrocytes derived from the transgenic ALS rat model.…”