IUPS/APS Newsroom March 29-April 6
San Diego Convention Center
Hall E Registration Area/Flex Unit
Telephone: 619.525.6228
Contact: Donna Krupa
(703) 967-2751 (cell)
(301) 634-7209 (office, outside IUPS dates)
Is There a New
Anti-Obesity “Second Messenger” Hiding in Our Cells? NAADP Shows Fast,
Dose-Related Impact on Satiety Cycle
Could NAADP/cholecystokinin-combo
attack fat from inside and out?
San Diego (April 3, 2005) – One traditional approach to
pharmaceutical design uses so-called “first messengers” – hormones, other
natural facilitators or synthetic products – to initiate various cellular
cascades for the desired physiological effect. To date, despite concerted
efforts at all levels of research, this approach has failed to develop a
truly successful obesity drug to address this major global health problem.
Enter a recently discovered and already controversial
natural molecule called nicotinic acid adenine dinucleotide
phosphate (NAADP), which is active in cells from plants to humans.
NAADP is thought to be a so-called “second messenger,” because it works from
inside cells, rather than externally. However its mode operation remains
unknown – and controversial in several aspects.
Results of a new study “establishes NAADP as a new
second messenger, and the study of this novel molecule has potential to
extend its clinical significance, possibly as a candidate for treating
obesity,” according to the lead author, Michiko Yamasaki at the Department
of Pharmacology, University of Oxford, United Kingdom.
Yamasaki is presenting the research at the 35th
Congress of the International Union of Physiological Sciences in San Diego,
March 31 - April 5, 2005.
*Paper presentation and “controversy” appearance:
“Rapid, selective and dose-dependent elevation of the second messenger NAADP,”
12:30 p.m.-3 p.m. Tuesday April 5, Physiology 932.3/board #A438. On view
7:30 a.m. - 4 p.m.
In addition, Ms. Yamasaki was chosen to participate
in a special “controversy” session #654 of the Calcium Signaling Track on
April 4 in room 29C of the Convention Center beginning at 10:30; her
presentation is scheduled for 11:45 a.m.
The team working on the study was comprised of Michiko
Yamasaki, Grant Churchill and Antony Galione at the Department of
Pharmacology, University of Oxford; Sandip Patel at University College
London; and Jose M. Cancela at CNRS, Laboratoire de Neurobiologie Cellulaire
et Moleculaire, Gif-sur-Yvette, France.
Viagra is the best-known “second messenger”
targeting agent
One of the problems with many drugs is their
side-effects, which range from annoying to lethal. “The most fundamental
answer to solve safety and other issues,” Yamasaki said, “is increasing the
specificity of a drug, and NAADP could provide a key in the area of
obesity.”
In another therapeutic arena, she notes, Viagra is the
world’s most successful and recognized secondary messenger targeting drug to
reach the market.
Cholecystokinin, a first messenger, activates NAADP;
so which is ‘therapeutic?’
Several earlier drugs designed for obesity treatment
were chosen because they released a chemical – the hormone serotonin -- in
the brain that controls satiation, as well as mood and body temperature.
“More recently, another hormone, cholecystokinin, has been considered to be
a potential drug target,” Yamasaki noted. Cholecystokinin is a
naturally-occurring chemical synthesized both in the small intestine and in
the brain when eating.
Cholecystokinin is a first messenger that tells cells
to release digestive enzymes in the pancreas and to cause satiety in the
brain. “The more cholecystokinin that’s produced, the more digestive enzymes
are released and the more quickly your brain tells you that you’re full – or
at least satisfied. Indeed, it also could be a potential drug for the
treatment of obesity, Yamasaki noted.
“We have shown that cholecystokinin activates NAADP
production through a specific protein on the cell surface, the
cholecystokinin-A receptor. The existence of the cholecystokinin-A receptor
in the brain strongly implies a possible role of NAADP in cholecystokinin-induced
satiety,” Yamasaki said.
Methods, results and conclusions
The team worked on the theory that NAAPD mobilizes Ca2+
from lysome-related organelles and plays a crucial role in cholecystokinin-induced
Ca2+ mobilization in pancreatic acinar cells. Despite the
intensive study into the physiological role of NAADP in Ca2+
signaling in pancreatic anicar cells, direct demonstration of changes in
NAADP levels in response to agonist-stimulations has been lacking, Yamasaki
said.
“We found that application of cholecystokinin to
isolated populations of pancreatic acinar cells caused NAAPD level to
increase as much as 6-fold in only 5 to 10 seconds,” Yamasaki said. The
cholecystokinin-A receptor, expressed predominantly in pancreatic acinar
cells, has two binding sites, one of high and one of low affinity.
“Unequivocal evidence that NAADP is a crucial
messenger”
“Intriguingly, the plot of NAADP level versus
cholecystokinin concentration was best fit with a two-site model, suggesting
that both the high- and low-affinity sites were linked to NAADP production,”
Yamasaki said. In contrast to the hormone cholecystokinin, the
neurotransmitter acetylcholine failed to affect NAADP level, even when
applied at supramaximal concentrations in terms of physiological relevance
and which saturate the calcium amplitude and spiking frequency.
In conclusion, Yamasaki said, “Our data in this
experiment provides the first direct evidence that cholecystokinin elicits a
rapid, dose-dependent and selective increase in NAADP, and thus unequivocal
evidence that NAADP is a crucial messenger employed by cholecystokinin.”
Yamasaki noted that NAADP has “a short history compared
to other traditional intracellular messengers and many aspects of this
molecule remain under investigation. However the potential of this new
messenger as a therapeutic target should not be underestimated,” she added.
***
The 35th Congress of the International Union of
Physiological Sciences is in San Diego, March 31 - April 5, 2005. The
Congress (http://www.iups2005.org/)
is organized by the six member societies of the U.S. National Committee of
the IUPS,
the American Physiological Society,
the Society for Neuroscience,
the Microcirculatory Society,
the Society of General Physiologists,
the Biomedical Engineering Society, and
the Society for Integrative and Comparative Biology, under the auspices
of the U.S. National Academy of Sciences.
The IUPS conference, held every four years, runs
concurrently this year with Experimental Biology 2005 at the San Diego
Convention Center.
The American Physiological Society (APS), which is
hosting IUPS, was founded in 1887 to foster basic and applied science, much
of it relating to human health. The Bethesda, MD-based Society has more than
10,000 members and publishes nearly 4,000 articles every year in its 14
peer-reviewed journals. In May, APS received the Presidential Award
for Excellence in Science, Mathematics and Engineering Mentoring (PAESMEM).
***
Editor’s Note: For further information or to
schedule an interview with a member of the research team, please contact
Donna Krupa at the IUPS/APS newsroom @ 619.525.6228 (March 31-April
6), or (703) 967-2751 (cell) or (301) 634-7209 (office), or Stacy Brooks at
240.432.9697 (cell) or 301.634.7253 (office).
A searchable online program for IUPS and EB is at
http://www.faseb.org/meetings/eb2005/call/default.htm
