Pituitary adenylate cyclase-activating polypeptide receptor activation in the hypothalamus recruits unique signaling pathways involved in energy homeostasis

Pituitary adenylate cyclase activating polypeptide (PACAP) exerts pleiotropic effects on ventromedial nuclei (VMN) of the hypothalamus and its control of feeding and energy expenditure through the Type I PAC1 receptor. However, the endogenous role of PAC1R's in the VMN and the downstream signaling responsible for PACAP's effects on energy balance are unknown. Numerous studies have revealed that PAC1Rs are coupled to both Gas/ adenylate cyclase/protein kinase A (Gas/AC/PKA) and Gaq/phospholipase C/protein kinase C (Gaq/PLC/PKC), while also undergoing trafficking following stimulation. To determine the endogenous role PAC1R's and downstream signaling that may explain PACAP's pleiotropic effects, we used RNA interference to knockdown VMN PAC1Rs and pharmacologically inhibited PKA, PKC and PAC1R trafficking. Knocking down PAC1Rs increased meal sizes, reduced total number of meals, and induced body weight gain. Inhibition of either PKA or PKC alone in awake male Sprague Dawley rats, attenuated PACAP's hypophagic and anorectic effects during the dark phase. However, PKA or PKC inhibition potentiated PACAP's thermogenic effects during the light phase. Analysis of locomotor activity revealed that PKA inhibition augmented PACAP's locomotor effects, however, PKC inhibition had no effect. Finally, PACAP infusion in the VMN induces surface PAC1R trafficking into the cytosol which was blocked by endocytosis inhibitors. Subsequently, inhibition of PAC1R trafficking into the cytosol attenuated PACAP-induced hypophagia. These results revealed that endogenous PAC1Rs uniquely engage PKA, PKC and receptor trafficking to mediate PACAP's pleiotropic effects in VMN control of feeding and metabolism.

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Progesterone Receptor Activation Mediates LH-Induced Type-I Pituitary Adenylate Cyclase Activating Polypeptide Receptor (PAC1) Gene Expression in Rat Granulosa Cells

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.2000.3667 ◽

2000 ◽

Vol 277 (1) ◽

pp. 270-279 ◽

Cited By ~ 29

Author(s):

Chemyong Ko ◽

Ok-Kyong Park-Sarge

Keyword(s):

Gene Expression ◽

Progesterone Receptor ◽

Adenylate Cyclase ◽

Granulosa Cells ◽

Receptor Activation ◽

Type I ◽

Pituitary Adenylate Cyclase

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A mutation in the second intracellular loop of the pituitary adenylate cyclase activating polypeptide type I receptor confers constitutive receptor activation

FEBS Letters ◽

10.1016/s0014-5793(00)01269-2 ◽

2000 ◽

Vol 469 (2-3) ◽

pp. 142-146 ◽

Cited By ~ 7

Author(s):

Yong-Jiang Cao ◽

Gerald Gimpl ◽

Falk Fahrenholz

Keyword(s):

Adenylate Cyclase ◽

Receptor Activation ◽

Type I ◽

Intracellular Loop ◽

Pituitary Adenylate Cyclase

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Pituitary adenylate cyclase activating polypeptide as a novel hypophysiotropic factor in fish

Biochemistry and Cell Biology ◽

10.1139/o00-055 ◽

2000 ◽

Vol 78 (3) ◽

pp. 329-343 ◽

Cited By ~ 63

Author(s):

Anderson OL Wong ◽

Wen Sheng Li ◽

Eric KY Lee ◽

Mei Yee Leung ◽

Lai Yin Tse ◽

...

Keyword(s):

Growth Hormone ◽

Protein Kinase C ◽

Protein Kinase ◽

Adenylate Cyclase ◽

Protein Kinase A ◽

Anterior Pituitary ◽

Kinase C ◽

Pituitary Adenylate Cyclase ◽

Pacap Receptors ◽

Kinase A

Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel member of the secretin-glucagon peptide family. In mammals, this peptide has been located in a wide range of tissues and is involved in a variety of biological functions. In lower vertebrates, especially fish, increasing evidence suggests that PACAP may function as a hypophysiotropic factor regulating pituitary hormone secretion. PACAP has been identified in the brain-pituitary axis of representative fish species. The molecular structure of fish PACAP is highly homologous to mammalian PACAP. The prepro-PACAP in fish, however, is distinct from that of mammals as it also contains the sequence of fish GHRH. In teleosts, the anterior pituitary is under direct innervation of the hypothalamus and PACAP nerve fibers have been identified in the pars distalis. Using the goldfish as a fish model, mRNA transcripts of PACAP receptors, namely the PAC1 and VPAC1 receptors, have been identified in the pituitary as well as in various brain areas. Consistent with the pituitary expression of PACAP receptors, PACAP analogs are effective in stimulating growth hormone (GH) and gonadotropin (GTH)-II secretion in the goldfish both in vivo and in vitro. The GH-releasing action of PACAP is mediated via pituitary PAC1 receptors coupled to the adenylate cyclase-cAMP-protein kinase A and phospholipase C-IP3-protein kinase C pathways. Subsequent stimulation of Ca2+ entry through voltage-sensitive Ca2+ channels followed by activation of Ca2+-calmodulin protein kinase II is likely the downstream mechanism mediating PACAP-stimulated GH release in goldfish. Although the PACAP receptor subtype(s) and the associated post-receptor signaling events responsible for PACAP-stimulated GTH-II release have not been characterized in goldfish, these findings support the hypothesis that PACAP is produced in the hypothalamus and delivered to the anterior pituitary to regulate GH and GTH-II release in fish.Key words: PACAP, VIP, PAC1 receptor, VPAC1 receptor, VPAC2 receptor, growth hormone, gonadotropin-II, cAMP, protein kinase A, protein kinase C, calcium, pituitary cells, goldfish, and teleost.

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