CATIONIC MODULATION OF 5-HT2 AND 5-HT3 RECEPTORS IN RAT SENSORY NEURONS - THE ROLE OF K+, CA2+ AND MG2+

The effects of changes in external K+, Ca2+, and Mg2+ concentrations o n 5-HT2- and 5-HT3 receptor-mediated depolarizations of the resting me mbrane potential in rat dorsal root ganglion (DRG) cells was studied. In cells exhibiting a (5)-HT2-mediated response, 5-HT and alpha-methyl 5-HT depolarized the resting membrane potential (RMP) and increased t he slope of the current-voltage (I/V) relationship. The equilibrium po tential (E-r) for the depolarization was linearly related to the logar ithm of the [K+](o), indicating the depolarization resulted from a dec rease in resting K+ conductance. In a subpopulation of large-diameter acutely dissociated DRG neurons recorded from using the whole-cell pat ch-clamp configuration, 5-HT produced an inward shift in the current r equired to hold cells at -60 mV. This inward shift in holding current was associated with a reduction in membrane conductance and reversed n ear E-k. This data suggests that the 5-HT2 receptor-mediated depolariz ation and increase in R-in seen in intact DRG preparation is produced by blockade of an outward K+ leak current. Increases in [K+](o) reduce d the increase in R-in and depolarization induced by 5-HT with 50% inh ibition of the depolarization occurring at 8.3 mM of [K+](o). Half-nor mal Ca2+ (1.2 IIM) produced a downward shift of the 5-HT concentration -response curve, reducing the maximal response by 40%, with minimal ef fect on the half maximal response. Mg2+ ions did not affect this 5-HT response. In cells exhibiting a 5-HT3 receptor response, 5-HT and 2-me thyl-5-HT produced depolarization with decreased R-in. The E-r for thi s depolarizing response (-30.2 +/- 1.8 mV) became less negative (-11.5 mV) in 10 mM [K+](o) with minimal effect on the amplitude of the depo larization. In Na+-free superfusate, the 5-HT-induced depolarization w as converted to hyperpolarization. This indicated the 5-HT3 response i ncreased a mixed Na+/K+ conductance. Elevated Ca2+ or Mg2+ markedly re duced the 5-HT3 response. Incubation with 3.5 mM Ca2+ shifted the 5-HT concentration-response curve downward and to the right, decreasing th e maximal response by 49% and increasing the EC50 by 10-fold. Elevated Mg2+ produced similar effects. In cells where both 5-HT2- and 5-HT3-m ediated responses could be demonstrated, the elevation of K+ or the re duction of Ca2+ converted a 5-HT2 response to a 5-HT2 response. The ab ove data suggest that elevation of [K+](o) or reduction of [Ca2+] prod uced by rapid firing rates of sensory neurons will favor the expressio n of 5-HT3 responses over 5-HT2 responses. (C) 1997 Elsevier Science B .V.