Tissue‐specific and Developmental Expression of Pituitary Adenylate Cyclase‐activating Polypeptide (PACAP) Receptors in Rat Brain

Abstract

The two forms of pituitary adenylate cyclase-activating polypeptide, PACAP27,and PACAP38, are novel members of the vasoactive intestinal peptide (VIP)/secretin/glucagon family of peptides. PACAP receptors that are positively coupled to adenylate cyclase and phospholipase C have been recently identified. We examined the expression of PACAP receptors in the rat cortex, hippocampus, cerebellum and hypothalamus during postnatal development. Functional studies revealed PACAP stimulation of cAMP formation in all the brain areas examined and [3H]inositol monophosphate ([3H]InsP) accumulation only in the cerebellum and hypothalamus. Throughout development, the efficacy or PACAP in stimulating cAMP formation slightly increased in the cortex and hypothalamus and decreased in the hippocampus and cerebellum; PACAP stimulation of [3H]InsP formation decreased in the cerebellum and remained steady in the hypothalamus. The effects of PACAP27 and PACAP38 on cAMP levels and inositol phospholipid hydrolysis were dose-dependent between 1 and 100 nM. In the same brain areas, treatment with VIP increased cAMP formation at doses greater than 100nM and failed to affect [3H]InsP content, thus suggesting the existence of type-1 PACAP receptors. The reverse transcription polymerase chain reaction (RT-PCR) was used to analyse the mRNA expression of type-1 PACAP receptor splice variants. PACAP receptor gene expression in the central nervous system was regulated in a developmental- and tissue-specific manner. The PACAP-R transcript was detected in all the brain areas examined whereas PACAP-R-hop mRNA ocurred only in the cerebellum and hypothalamus. The different expression profiles and functional properties of PACAP receptors in the developing rat brain suggest an involvement of PACAP in histogenesis, maturation and neurotransmission.

Development-Related Splicing Regulates Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Receptors in the Retina

“…Changes in PAC1 isoform expression have been reported in the cerebellum and suprachiasmatic nucleus, as well as in the cortex. 30,35,36 However, very little information describing the expression of PACAP receptors in the developing mammalian retina can be found, which provides the rationale for our study. Therefore, we harvested retina tissues on P0, P1, P3, P5, P10, P15, and P20, covering all important developmental stages, to assess the expression changes of the major PACAP receptors.…”

Opposing mitogenic regulation by PACAP in sympathetic and cerebral cortical precursors correlates with differential expression of PACAP receptor (PAC1-R) isoforms

“…express the hop receptor isoform, whereas the short isoform is expressed later as neurons migrate and establish synaptic connections (D'Agata et al, 1996;Villalba et al, 1997). We speculate that changes in receptor isoforms may also contribute to cortical neurogenesis, as precursors exit the cell cycle, and neurons migrate to establish layer-specific differentiation.…”

“…While we detected primarily the short PAC 1 -R isoform in E13.5 cortex, small amounts of hop isoform were present, raising the possibility that after cells exit the mitotic cycle, receptor isoforms change, mediating subsequent PACAP stimulation of neuronal differentiation, an issue under current investigation. More generally, both granule precursors (D'Agata et al, 1996) and symapthetic neuroblasts express the hop isoform as they proliferate, whereas cortical precursors exhibit the short receptor subtype, providing additional evidence of region-specific patterns of PAC 1 -R expression during nervous system ontogeny.…”

Duplicated receptors for VIP and PACAP (VPAC1R and PAC1R) in a teleost fish, Fugu rubripes

“…It shows a wide tissue distribution in mammals, notably in the brain and in peripheral organs such as the pancreas, gonads and respiratory and urogenital tracts (Vaudry et al 2000c). Similarly, the PACAP type 1 receptor shows a broad spectrum of tissue expression, however it is predominantly expressed in the CNS (D'Agata et al 1996, Basille et al 2000 where it is thought to act not only as a hypophysiotropic hormone, but also as a neurotransmitter and/or neuromodulator (Hashimoto et al 1993, Ogi et al 1993, Peeters et al 1999. The correlation between ligand and receptor distribution is more difficult to make in the case of PACAP compared with the VIPs, as the PACAP ligand can also interact with the VIP receptors.…”