Jianguo G' Gu

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Therapeutic target for treatment of asthma and
other respiratory diseases
Jianguo G. Gu Department of Oral and
Maxillofacial Surgery McKnight Brain Institute
and College of Dentistry, University of
Florida Tel [phone] E-mail
jgu_at_dental.ufl.edu http//plaza.ufl.edu/jggjgg
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Cold and Asthma
1. Cold air can exacerbate asthma and directly
trigger asthma attacks. 2. Inhalation of cold
air is a direct cause of airway constriction in
athletes performing winter sports, i.e. exercise
asthma. 3. Clinically, the cold air challenge
test, a test of respiratory airway reactivity
and airway resistance, has been used for asthma
diagnosis for over 20 years.
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Vagal afferent nerves, cold, and asthma

• Respiratory visceral afferent neurons in the
  vagus nerve regulate respiratory functions
  through central and local reflexes
• Cold air can rapidly provoke respiratory
  reactions, particularly in people who are
  susceptible to asthma
• We asked whether respiratory airway vagal
  afferent neurons can be stimulated by cold
  stimuli and if so, what molecular substrate
  mediates this autonomic nerve response.

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Cold-sensing receptors
Conscious sensations of skin cooling have been
thought to be mediated in part by TRPM8
(Transient Receptor Potential M8), a newly
identified membrane ion channel expressed in the
somatic sensory system (McKemy et al, 2002)
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Temperature-sensing molecules
Caterina et al (1997) The capsaicin receptor a
heat-activated ion channel in the pain pathway.
Nature. 389816-24. Caterina et al. (1999) A
capsaicin-receptor homologue with a high
threshold for noxious heat.. Nature.
398(6726)436-41. McKemy et al. (2002)
Identification of a cold receptor reveals a
general role for TRP channels in thermosensation.
Nature. 41652-8. Peier et al. (2002) A TRP
channel that senses cold stimuli and menthol.
Cell. 108705-15. Xu et al. (2002) TRPV3 is a
calcium-permeable temperature-sensitive cation
channel. Nature. 418181-6. Guler et al. (2002)
Heat-evoked activation of the ion channel, TRPV4.
J Neurosci. 226408-14. Story et al. (2003)
ANKTM1, a TRP-like channel expressed in
nociceptive neurons, is activated by cold
temperatures. Cell. 112819-29.
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Menthol- and cold-induced currents on cultured
DRG neurons
DRG dorsal root ganglion primary sensory
afferents
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Respiratory airway vagal afferent neurons can be
stimulated by cold stimuli
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Vagal afferent neurons express cold receptors
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Respiratory airway vagal afferent neurons
response to cold stimuli via activation of TRPM8
receptors
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TRPM8 as a therapeutic target for treatment of
asthma and other respiratory diseases
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Acknowledgement Hong Xing Kenzo
Tsuzuki Jennifer Ling Meng Chen Richard Johnson
Charles Vierck Makoto Tominaga David Julius