Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors
Abstract
:1. Introduction—Physiological Roles of the PACAP and VIP Receptors
2. Pharmacology of PACAP and VIP Receptors
2.1. Binding Characteristics of Natural Peptides Differentiating the PACAP Subfamily of Receptors
Selective Peptide Analogues of PAC1R, VPAC1R, and VPAC2R
2.2. Signaling Characteristics of PAC1R, VPAC1R, and VPAC2R
2.2.1. Alternative Splicing
2.2.2. Signaling via Gs Coupling
2.2.3. Signaling via Gq/11 and Gi/o Coupling
2.2.4. Non-G Protein Signaling
ADP-Ribosylation Factor
Endosomal Signaling
2.2.5. Additional Downstream Signal Transduction Pathways
Ion Channels
Transactivation of Epidermal Growth Factor Receptor (EGFR)
MAPK/ERK Signal Transduction
2.2.6. Receptor Activity-Modifying Proteins (RAMPs)
2.3. Receptor Desensitisation and Recycling
2.4. Understanding of PACAP and VIP Signaling and Regulation That Needs to Be Addressed for Disease-Focused Therapies
3. Molecular Activation of PACAP and VIP Receptors
3.1. Structural Characteristics of the PACAP Subfamily of Receptors
3.2. Characteristics of the PACAP-Bound VPAC1R, VPAC2R, and PAC1R Structures
3.3. Characteristics of the Maxadilan-Bound PAC1R Structure
3.4. Activation Characteristics of the PACAP Subfamily of Receptors
3.5. Allosteric Modulation
4. Concluding Remarks
Author Contributions
Funding
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Receptor | Distribution | Physiological/Therapeutic Role |
---|---|---|
VPAC1R | CNS [35] (cerebral cortex [36,37], hypothalamus [38], hippocampus [36,39]) | Control of circadian rhythm [38], learning, and memory [39] |
Liver [40] | Glucose metabolism [41,42] | |
Lung [40,43] | Asthma and COPD (relaxation of airway and vascular smooth muscles [44], anti-inflammatory effect [45,46], and regulation of mucus secretion [47]), chronic bronchitis [48] | |
Intestine [40,49] | Peristalsis, ion transport and mucus secretion [11,12,50] | |
Breast [40] | Cell proliferation in cancer [51,52] | |
T-lymphocytes and macrophages (constitutively expressed) [53,54,55,56] | Immune regulation [32,33] | |
VPAC2R | CNS [35] (thalamus [57,58,59], suprachiasmatic nucleus [29,31,57,59], dentate gyrus [59], amygdala [57]) | Schizophrenia [60,61,62], brain injury [63], control of circadian rhythm [29,30,31], processing of fear-related memory [64] |
Smooth muscles [65] | Vasodilation (blood vessels) [66], erectile dysfunction (male reproductive system) [67] | |
Pancreas [68] | Insulin secretion [34] | |
Lungs [65,69] | Asthma and COPD (relaxation of airway and vascular smooth muscles [44,70], anti-inflammatory effect [45,46], and regulation of mucus secretion [47]), pulmonary arterial hypertension [71], chronic bronchitis [48] | |
T-lymphocytes and macrophages (expressed upon cell activation) [53,54,56] | Immune regulation [72] | |
PAC1R | CNS [35] (olfactory bulb [16,73], cerebral cortex, thalamus [73], hypothalamus [73,74], hippocampus, amygdala [73,75], substantia nigra [73], cerebellum [73] | Astrocyte proliferation [76], appetite and feeding behaviour [77,78], anxiety [79], stress response [80,81,82], control of circadian rhythm [20], post-traumatic stress disorder [83], traumatic brain injury [84], migraine [85], Alzheimer’s disease [86,87] |
Embryonic nervous system [88,89] | Neuronal differentiation of neural progenitor and embryonic stem cells [90,91,92] | |
Eyes (corneal endothelium [93], retina [94], lacrimal gland [95] | Maintenance of corneal endothelial barrier integrity [93] Protection against retinopathy [94,96] Stimulation of tear production [95] | |
Bone marrow (haematopoietic progenitor cells) [97] | Haematopoiesis [97] | |
Adrenal medulla | Adrenal catecholamine secretion [98] | |
Pancreas | Insulin secretion [99] | |
Cardiac neurons [100] | Modulates excitability—stimulatory effect on CV system [100] | |
Bladder | Urinary bladder dysfunction [101] |
Selective Receptor | Compound | Agonist/Antagonist | Peptide Modifications | Relative Selectivity * | Reference |
---|---|---|---|---|---|
VPAC1R | [Tyr9,Dip18]-VIP | Agonist | VIP analogue | VPAC1R ([125I]VIP Ki = 0.1 nM) VPAC2R ([125I]VIP Ki = 53 nM) PAC1R ([125I]PACAP27 Ki = 3 μM) | [140] |
[Ala22]-VIP | Agonist | VIP analogue | VPAC1R ([125I]VIP IC50 = 10 nM), VPAC2R ([125I]RO 25-1553 IC50 = 1 μM) | [141,142] | |
[Leu22]-VIP | Agonist | VIP analogue | VPAC1R ([125I]VIP IC50 = 11 nM), VPAC2R ([125I]RO 25-1553 IC50 = 700 nM) | [143] | |
[Ala11,22,28]-VIP | Agonist | VIP analogue | VPAC1R (cAMP EC50 < 1 nM) VPAC2R (cAMP EC50 > 1 µM) | [142] | |
[Arg16]-PACAP (1–23) | Agonist | C-terminal truncated PACAP analogue | VPAC1R ([125I]VIP IC50 = 2.5 nM), VPAC2R ([125I]RO 25-1553 IC50 = 1.2 µM) | [143] | |
Chicken [Arg16]-secretin | Agonist | Secretin analogue | PAC1R ([125I]Ac-His1-PACAP27 IC50 = 30 µM) VPAC1R ([125I]VIP IC50 = 100 nM), VPAC2R ([125I]VIP IC50 = 10 µM) 1 | [144] | |
[Lys15, Arg16, Leu27]-VIP(1-7)/GRF(8-27) | Agonist | Chimeric VIP/GRF analogue | VPAC1R ([125I]VIP IC50 = 1 nM), VPAC2R ([125I]VIP IC50 > 30 µM) 2 | [144] | |
PG 97-269 | Antagonist | N-terminal modified VIP/GRF chimeric analogue | VPAC1R ([125I]VIP IC50 = 2 nM), VPAC2R ([125I]VIP IC50 = 3 μM) | [145] | |
VPAC2R | RO 25-1392 | Agonist | Cyclic VIP analogue | VPAC1R ([125I]VIP Ki = 1 μM), VPAC2R ([125I]VIP Ki = 9.6 nM) | [146] |
RO 25-1553 | Agonist | Cyclic VIP analogue | VPAC1R ([125I]VIP IC50 = 800 nM), VPAC2R ([125I]RO 25-1553 IC50 = 1 nM) | [147] | |
PG 96-249 | Agonist | Linear RO 25-1553 analogue | VPAC1R ([125I]VIP IC50 = 3 μM), VPAC2R ([125I]RO 25-1553 IC50 = 10 nM) | [147] | |
BAY 55-9837 | Agonist | PACAP/VIP analogue | PAC1R ([125I]PACAP27 IC50 = N/A) 3 VPAC1R ([125I]PACAP27 IC50 = 8.7 µM), VPAC2R ([125I]PACAP27 IC50 = 60 nM) | [34] | |
PG 99–465 | Antagonist | N-terminal myristoylated, C-terminal elongated VIP analogue | VPAC1R ([125I]VIP IC50 = 200 nM), VPAC2R ([125I]RO 25-1553 IC50 = 1 nM) | [147] | |
PAC1R | M65 | Antagonist | Maxadilan analogue | PAC1R ([125I]PACAP27 Kd = 0.6 nM), VPAC1R ([125I]VIP Kd = N/A), VPAC2R ([125I]VIP Kd = N/A) 4 | [133] |
max.D.4 | Antagonist | Maxadilan analogue | PAC1R ([125I]PACAP27 Kd = 0.6 nM), VPAC1R ([125I]VIP Kd = N/A), VPAC2R ([125I]VIP Kd = N/A) 4 | [148] | |
PACAP(6-38) | Antagonist | N-terminal truncated PACAP analogue | PAC1R ([125I]Ac-His1-PACAP27 Ki = 30 nM), VPAC1R ([125I]VIP Ki = 600 nM), VPAC2R ([125I]Ac-His1-PACAP27 Ki = 40 nM) 5 | [149,150] |
N-Terminal Truncation/Modification | ||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 5 | 10 | 15 | 20 | 25 | 30 | 35 | |||||||||||||||||||||||||||||||
PACAP38 | H | S | D | G | I | F | T | D | S | Y | S | R | Y | R | K | Q | M | A | V | K | K | Y | L | A | A | V | L | G | K | R | Y | K | Q | R | V | K | N | K |
PACAP(6–38) | H | S | D | G | I | F | T | D | S | Y | S | R | Y | R | K | Q | M | A | V | K | K | Y | L | A | A | V | L | G | K | R | Y | K | Q | R | V | K | N | K |
VIP | H | S | D | A | V | F | T | D | N | Y | T | R | L | R | K | Q | M | A | V | K | K | Y | L | N | S | I | L | N | ||||||||||
PG 97-269 1 | H | F | D | A | V | F | T | N | S | Y | R | K | V | L | K | R | L | S | A | R | K | L | L | Q | D | I | L | |||||||||||
PG 99-465 2 | H | S | D | A | V | F | T | D | N | Y | T | K | L | R | K | Q | M | A | V | K | K | Y | L | N | S | I | K | K | G | G | T |
C-Terminal Truncation/Elongation | ||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 5 | 10 | 15 | 20 | 25 | 30 | 35 | |||||||||||||||||||||||||||||||
PACAP38 | H | S | D | G | I | F | T | D | S | Y | S | R | Y | R | K | Q | M | A | V | K | K | Y | L | A | A | V | L | G | K | R | Y | K | Q | R | V | K | N | K |
[R16]-PACAP(1–23) | H | S | D | G | I | F | T | D | S | Y | S | R | Y | R | R | Q | M | A | V | K | K | Y | L | A | A | V | L | G | K | R | Y | K | Q | R | V | K | N | K |
VIP | H | S | D | A | V | F | T | D | N | Y | T | R | L | R | K | Q | M | A | V | K | K | Y | L | N | S | I | L | N | ||||||||||
RO 25-1553 1 | H | S | D | A | V | F | T | E | N | Y | T | K | L | R | K | Q | L | A | A | K | K | Y | L | N | D | L | K | K | G | G | T | |||||||
PG 96-249a 2 | H | S | D | A | V | F | T | E | N | Y | T | K | L | R | K | Q | L | A | A | K | K | Y | L | N | D | L | K | K | G | G | T |
Receptor | Region | Agonist | PDB | Resolution | Method |
---|---|---|---|---|---|
VPAC2R [296] 1 | ECD | – | 2X57 | 2.1 Å | X-ray diffraction |
PAC1sR [297] | ECD | – | 3N94 | 1.8 Å | X-ray diffraction |
PAC1sR [298] | ECD | PACAP (6–38) | 2JOD | – | Solution NMR |
Receptor | Agonist | G Protein 1 | PDB | Resolution |
---|---|---|---|---|
PAC1nR [135] | PACAP38 | DNGαs, Gβ1, Gγ2 | 6P9Y | 3.0 Å |
PAC1nR [139] | PACAP38 | Mini-Gαs, Gβ1, Gγ2 | 6LPB | 3.9 Å |
PAC1sR [138] | PACAP38 | DNGαs, Gβ1, Gγ2 | 6M1I | 3.5 Å |
PAC1sR [138] | Maxadilan | DNGαs, Gβ1, Gγ2 | 6M1H | 3.6 Å |
VPAC1R-LgBiT 2 [136] | PACAP27 | DNGαs, Gβ1-HiBiT, Gγ2 | 6VN7 | 3.2 Å |
VPAC2R-LgBiT 2 [137] | PACAP27 | DNGαs, Gβ1-HiBiT, Gγ2 | 7VQX 3 | 2.7 Å |
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Lu, J.; Piper, S.J.; Zhao, P.; Miller, L.J.; Wootten, D.; Sexton, P.M. Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors. Int. J. Mol. Sci. 2022, 23, 8069. https://doi.org/10.3390/ijms23158069
Lu J, Piper SJ, Zhao P, Miller LJ, Wootten D, Sexton PM. Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors. International Journal of Molecular Sciences. 2022; 23(15):8069. https://doi.org/10.3390/ijms23158069
Chicago/Turabian StyleLu, Jessica, Sarah J. Piper, Peishen Zhao, Laurence J. Miller, Denise Wootten, and Patrick M. Sexton. 2022. "Targeting VIP and PACAP Receptor Signaling: New Insights into Designing Drugs for the PACAP Subfamily of Receptors" International Journal of Molecular Sciences 23, no. 15: 8069. https://doi.org/10.3390/ijms23158069