PACAP's Journey From Brain Mystery to Medical Marvel
11th International Symposium on VIP, PACAP and Related Peptides | 27–31 August 2013 | PÉCS, HUNGARY
In the picturesque city of Pécs, Hungary, where Mediterranean atmosphere meets Central European heritage, scientists gathered in late August 2013 for a remarkable scientific meeting. The 11th International Symposium on VIP, PACAP and Related Peptides brought together researchers from across the globe, all united by their fascination with a family of tiny biological molecules with enormous medical potential. At the heart of their discussions was pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide that might be one of our body's most versatile messengers, yet remains largely unknown outside scientific circles 2 .
PACAP was first discovered in 1989 by Akira Arimura and his team, who identified it in hypothalamic extracts based on its ability to stimulate cAMP production in pituitary cells.
This symposium, held at the cutting-edge János Szentágothai Research Center, continued a tradition dating back to the early 1990s—a testament to the growing importance of these peptides in understanding human health and disease 8 . The researchers shared findings that would push the boundaries of how we understand everything from migraine headaches to infant death syndrome, from retinal degeneration to intestinal inflammation. Their work represents a fascinating frontier in neuroscience and medicine—where tiny molecules exert powerful influences on our wellbeing, and where scientific collaboration across borders might hold the key to unlocking new treatments for challenging conditions 2 3 .
PACAP was first discovered in 1989 by Akira Arimura and his team, who identified it in hypothalamic extracts based on its ability to stimulate cAMP production in pituitary cells 3 . This breakthrough revealed a new member of the secretin/glucagon/VIP peptide family, which includes several important regulatory molecules.
PACAP exists in two forms: PACAP-38 (with 38 amino acids) and PACAP-27 (with 27 amino acids), with the former being the predominant form in mammals 6 .
What makes PACAP particularly fascinating to researchers is its pleiotropic nature—its ability to perform multiple functions in different contexts. Unlike many biological molecules that have specialized roles, PACAP appears to be a true multitasker 3 4 :
These peptides function as crucial signaling molecules in the nervous system and beyond. They bind to specific receptors on cell surfaces—PAC1, VPAC1, and VPAC2—triggering cascades of cellular activity that influence everything from energy metabolism to neuronal survival 3 . The receptors themselves are fascinating examples of biological specificity; while PAC1 binds primarily to PACAP, VPAC1 and VPAC2 respond to both PACAP and VIP (vasoactive intestinal peptide), allowing for complex regulatory networks within the body 4 .
This functional diversity stems from PACAP's widespread distribution throughout the body—it's found not only in the brain but also in peripheral organs, the digestive system, respiratory system, and even the skin 3 .
The 11th International Symposium held in Pécs was particularly meaningful because of the city's connection to PACAP research history. The University of Pécs had maintained a long-standing collaboration with the US-Japan Biomedical Research Laboratories led by Dr. Arimura, the very scientist who first discovered PACAP 2 .
The conference was hosted by the PACAP Research Team of the University of Pécs and Hungarian Academy of Sciences, which had been conducting PACAP research for over a decade 2 .
The symposium attracted leading international researchers including:
among others 2 . This global representation highlighted the worldwide interest in PACAP research and its implications for human health.
While the full abstracts were published in the Journal of Molecular Neuroscience 1 , several key themes emerged throughout the symposium:
Multiple presentations explored how PACAP could shield nervous tissue from damage in conditions like stroke, Parkinson's disease, and traumatic brain injury.
Unlike previous symposia that focused mainly on PACAP's neural functions, significant attention was paid to its protective roles in peripheral organs and systems 3 .
Researchers presented new insights into how PACAP receptors function and how they might be targeted for therapeutic purposes.
Evidence emerged showing how PACAP shapes early development and how its disruption might contribute to various disorders.
The symposium particularly emphasized the translational potential of PACAP research—how laboratory findings might be transformed into clinical applications for patients suffering from various conditions 3 4 .
One of the most compelling discussions at the symposium likely centered on PACAP's role in migraine headaches—a debilitating condition affecting millions worldwide. Emerging evidence had shown that PACAP levels were elevated in migraine patients and that administering PACAP could actually trigger migraine-like headaches in both healthy volunteers and migraine sufferers 6 .
This connection represented both a scientific puzzle and a potential therapeutic opportunity. If researchers could understand how PACAP influenced migraine pathways, they might develop new treatments to block these effects and relieve suffering.
A fascinating study presented at the symposium (or closely related to its themes) came from researchers at the University of Pécs, who designed an elegant experiment to unravel how PACAP influences trigeminal ganglion cells—the key players in migraine pathology 6 .
The team employed a sophisticated transcriptomic analysis approach to understand the gene expression changes induced by PACAP in these critical cells.
The research team followed a meticulous experimental design:
The findings revealed fascinating patterns of gene expression changes:
| Gene Symbol | Gene Name | PACAP-38 Fold Change | PACAP(6-38) Fold Change | Potential Function |
|---|---|---|---|---|
| Ndufb6 | NADH:ubiquinone oxidoreductase subunit B6 | -50.7 | -80.9 | Mitochondrial energy production |
| Trpm8 | Transient receptor potential cation channel subfamily M member 8 | +4.3 | +5.1 | Cold sensation, migraine pathogenesis |
| Cenpb | Centromere protein B | +3.2 | +3.5 | Chromosome segregation |
| Gnal | G protein subunit alpha L | +2.8 | +3.1 | Signal transduction |
| Hsp90aa1 | Heat shock protein 90 alpha family class A member 1 | +2.6 | +2.9 | Cellular stress response |
The most striking finding was the dramatic downregulation of Ndufb6, a gene critical for mitochondrial function, and the significant upregulation of Trpm8, a channel protein known to be involved in cold sensation and migraine pathology 6 .
This experiment was particularly significant because it demonstrated that both PACAP-38 and its truncated form PACAP(6-38) produced similar effects—a surprising finding since PACAP(6-38) was traditionally considered a receptor antagonist that should block rather than mimic PACAP's actions 6 .
This suggested that PACAP might be acting through alternative receptors or different splice variants of known receptors than previously thought. The identification of these novel targets could open up new avenues for migraine treatment that might be more effective than current approaches 6 .
PACAP research relies on a sophisticated array of biological tools and experimental approaches. Here are some of the key reagents and their applications:
| Reagent | Function | Research Application |
|---|---|---|
| PACAP-38 | Native 38-amino acid form | Studying physiological effects, neuroprotection |
| PACAP-27 | Native 27-amino acid form | Comparing isoform specificity |
| PACAP(6-38) | Truncated form | Investigating receptor mechanisms, potential antagonist |
| PAC1 receptor antibodies | Identifying receptor distribution | Mapping expression patterns in tissues |
| VPAC1/VPAC2 receptor antibodies | Differentiating receptor types | Determining receptor specificity of effects |
| PACAP knockout mice | Animals lacking PACAP gene | Studying physiological consequences of PACAP deficiency |
| PAC1 receptor knockout mice | Animals lacking PAC1 receptor | Isolating PAC1-specific effects |
| RNA sequencing tools | Transcriptome analysis | Identifying gene expression changes |
| cAMP assays | Measuring second messenger activation | Monitoring receptor activation |
These tools have enabled researchers to unravel the complex functions of PACAP and its receptors, moving from basic biological understanding toward therapeutic applications 3 6 .
One of the most compelling medical connections discussed was the relationship between PACAP and sudden infant death syndrome (SIDS). Researchers had discovered that mice genetically engineered to lack PACAP or its primary receptor (PAC1) showed increased neonatal mortality during a developmental period equivalent to the human SIDS risk window 4 .
These PACAP-deficient mice appeared normal in many respects but demonstrated increased susceptibility to various metabolic and environmental challenges. Specifically, they showed problems with thermoregulation, breathing control, and cardiac adaptation—all factors implicated in SIDS cases 4 .
Interestingly, PACAP and VIP receptors are expressed on certain tumor cells, opening up diagnostic and therapeutic possibilities. Researchers including Mathew Thakur had developed patents for using PACAP and VIP peptides to detect circulating tumor cells in biological fluids—a promising approach for cancer diagnosis and monitoring .
Other investigators explored using radiolabeled VIP analogs for tumor imaging and therapy, taking advantage of the overexpression of VIP receptors on certain cancer cells. These approaches represented innovative strategies in the ongoing battle against cancer .
Beyond the brain, symposium presentations highlighted PACAP's protective roles throughout the body 3 :
| Organ System | Protective Effect | Potential Clinical Application |
|---|---|---|
| Digestive system | Reduces intestinal inflammation, protects against ulcer formation | Inflammatory bowel disease, ulcer treatment |
| Liver | Decreases inflammation and steatosis | Fatty liver disease, obesity-related liver damage |
| Respiratory system | Anti-inflammatory effects in airways | Asthma, chronic obstructive pulmonary disease |
| Skin | Modulates allergic and inflammatory responses | Psoriasis, contact dermatitis |
| Eyes | Protects retinal cells from damage | Diabetic retinopathy, age-related macular degeneration |
| Cardiovascular system | Protects against ischemia, oxidative stress | Heart attack, stroke prevention |
| Bones and joints | Prevents osteoarthritis and rheumatoid arthritis development | Arthritis treatment |
These widespread protective effects position PACAP as a potentially powerful therapeutic agent for conditions affecting virtually every organ system in the body 3 .
The 11th International Symposium on VIP, PACAP and Related Peptides in Pécs represented both a celebration of progress and a looking forward to future discoveries. The research presented demonstrated the astonishing range of biological processes influenced by this family of peptides—from fundamental developmental processes to sophisticated regulatory mechanisms in adults 2 3 .
As symposium chair Dora Reglodi and her team emphasized, the gathering was about more than just sharing data—it was about fostering scientific collaborations and inspiring the next generation of researchers to continue exploring the mysteries of these fascinating peptides.
The ongoing research into PACAP and related peptides continues to hold promise for understanding and treating some of medicine's most challenging conditions—from migraine to sudden infant death, from retinal degeneration to inflammatory bowel disease. As we look to the future, the work showcased in Pécs reminds us that sometimes the most powerful medical insights come from studying the smallest biological molecules—tiny peptides with tremendous potential for improving human health 3 4 .
As research continues, each symposium in this series adds another piece to the puzzle, moving us closer to harnessing the power of these remarkable peptides for therapeutic benefit. The 2013 meeting in Pécs certainly delivered on this promise, setting the stage for exciting developments in the years to follow 2 8 .