The long-term objective is to understand how multiple serotonin receptors, present on the same dorsal root ganglion cell, interact to synthesize a meaningful signal. To date, evidence indicates that 5-HT2 and 5-HT3 receptors co-occur on A-type cells, and that 5-HT1A and 5-HT(2 or 3) receptors are colocalized on C-type cells of the primary sensory neurons. The problem to be solved is how seemingly conflicting effects (e.g. co-occurrence of receptors that increase and decrease membrane conductance, or that depolarize and hyperpolarize the membrane) are integrated into a coherent signal. It is hypothesized that integration of multiple receptor signals is accomplished by second messenger cross-talk. Using a combination of current-clamp, voltage-clamp and patch-clamp methodologies on acutely isolated dorsal root ganglia or their dissociated cells, the ion currents affected by each 5-HT receptor subtype will be identified. Then, by use of pharmacological probes, the role of various known second messengers in transducing or modulating the ion current(s) associated with each receptor subtype will be characterized. Once the ion current(s) and the second messenger roles have been described for each receptor subtype, the interactions between receptor subtypes will be explored. Whenever it is observed that one receptor subtype will augment or impede the effect of another receptor subtype present on the same cell, the role of second messengers in that interaction will be characterized. The understanding of how one receptor subtype modulates the response of another receptor subtype on the same cell would markedly increase our ability to pharmacologically manipulate that cells responsiveness. With respect to the dorsal root ganglion cells, this understanding would increase opportunities for gaining selective pharmacological control over sensory input, including pain and motor reflexes. In addition, other cell systems in the brain contain multiple 5-HT receptor subtypes, and the principles established by this investigation have potential application in the larger area of serotonin pharmacology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030600-02
Application #
2268566
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1993-07-05
Project End
1994-10-31
Budget Start
1994-07-01
Budget End
1994-10-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
121911077
City
Chicago
State
IL
Country
United States
Zip Code
60612
Holohean, Alice M; Hackman, John C (2004) Mechanisms intrinsic to 5-HT2B receptor-induced potentiation of NMDA receptor responses in frog motoneurones. Br J Pharmacol 143:351-60
Valeyev, A Y; Hackman, J C; Holohean, A M et al. (1999) GABA-Induced Cl- current in cultured embryonic human dorsal root ganglion neurons. J Neurophysiol 82:1-9
Valeyev, A Y; Hackman, J C; Holohean, A M et al. (1999) Alphaxalone activates a Cl- conductance independent of GABAA receptors in cultured embryonic human dorsal root ganglion neurons. J Neurophysiol 82:10-5
Holohean, A M; Hackman, J C; Davidoff, R A (1999) Mechanisms involved in the metabotropic glutamate receptor-enhancement of NMDA-mediated motoneurone responses in frog spinal cord. Br J Pharmacol 126:333-41
Cardenas, C G; Del Mar, L P; Cooper, B Y et al. (1997) 5HT4 receptors couple positively to tetrodotoxin-insensitive sodium channels in a subpopulation of capsaicin-sensitive rat sensory neurons. J Neurosci 17:7181-9
Cardenas, C G; Del Mar, L P; Scroggs, R S (1997) Two parallel signaling pathways couple 5HT1A receptors to N- and L-type calcium channels in C-like rat dorsal root ganglion cells. J Neurophysiol 77:3284-96
Cardenas, C G; Del Mar, L P; Scroggs, R S (1995) Variation in serotonergic inhibition of calcium channel currents in four types of rat sensory neurons differentiated by membrane properties. J Neurophysiol 74:1870-9
Del Mar, L P; Cardenas, C G; Scroggs, R S (1994) Serotonin inhibits high-threshold Ca2+ channel currents in capsaicin-sensitive acutely isolated adult rat DRG neurons. J Neurophysiol 72:2551-4