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Volume 17, Number 10,
Issue of May 15, 1997
pp. 3525-3537
Copyright ©1997 Society for Neuroscience
The Role of Calcium in the Desensitization of Capsaicin Responses
in Rat Dorsal Root Ganglion Neurons
Received Sept. 26, 1997; revised Feb. 27, 1997; accepted March 6, 1997.
Patricia A. Koplas,
Robert L. Rosenberg, and
Gerry S. Oxford
Curriculum in Neurobiology and the Departments of Physiology and
Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill,
North Carolina 27599
Capsaicin (Cap) is a pungent extract of the
Capsicum pepper family, which activates nociceptive
primary sensory neurons. Inward current and membrane potential
responses of cultured neonatal rat dorsal root ganglion neurons to
capsaicin were examined using whole-cell and perforated patch recording
methods. The responses exhibited strong desensitization operationally
classified as acute (diminished response during constant Cap exposure)
and tachyphylaxis (diminished response to successive applications of
Cap). Both acute desensitization and tachyphylaxis were greatly
diminished by reductions in external Ca2+ concentration.
Furthermore, chelation of intracellular Ca2+ by addition of
either EGTA or
bis(2-aminophenoxy)ethane-N,N,N ,N-tetra-acetic acid to
the patch pipette attenuated both forms of desensitization even in
normal Ca2+. Release of intracellular Ca2+ by
caffeine triggered acute desensitization in the absence of extracellular Ca2+, and barium was found to effectively
substitute for calcium in supporting desensitization. Cap activated
inward current at an ED50 of 728 nM, exhibiting
cooperativity (Hill coefficient, 2.2); however, both forms of
desensitization were only weakly dependent on [Cap], suggesting a
dissociation between activation of Cap-sensitive channels and
desensitization. Removal of ATP and GTP from the intracellular
solutions resulted in nearly complete tachyphylaxis even with
intracellular Ca2+ buffered to low levels, whereas changes
in nucleotide levels did not significantly alter the acute form of
desensitization. These data suggest a key role for intracellular
Ca2+ in desensitization of Cap responses, perhaps through
Ca2+-dependent dephosphorylation at a locus that normally
sustains Cap responsiveness via ATP-dependent phosphorylation. It also seems that the signaling mechanisms underlying the two forms of desensitization are not identical in detail.
Key words:
capsaicin;
sensory neurons;
patch clamp;
desensitization;
calcium;
nociceptors;
dorsal root ganglion
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