Graduation Year

2005

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Pharmacology and Therapeutics

Major Professor

Javier Cuevas, Ph.D.

Co-Major Professor

Lynn Wecker, Ph.D.

Committee Member

Craig Doupnik, Ph.D.

Committee Member

Jahanshah Amin, Ph.D.

Committee Member

Keith Pennypacker, Ph.D.

Keywords

Calcium channel, Potassium channel, Sodium channel

Abstract

Sigma receptors have been implicated in the regulation of the cardiovascular system. Some of the cardiovascular effects of sigma receptors may be through the modulation of autonomic neurons. Studies on the expression and cellular function of sigma receptors in autonomic neurons were conducted in neonatal rat intracardiac (ICG) and superior cervical ganglia (SCG).

Individual neurons from SCG and ICG were shown to express transcripts encoding the sigma-1 receptor. The effects of sigma receptors activation on high-voltage-activated Ca2+ channels was studied in isolated neurons of these ganglia. Bath application of sigma receptor agonists depressed peak calcium channel currents in a dose-dependent manner and the rank order potency of haloperidol> ibogaine > (+)-pentazocine > DTG is consistent with the effects being mediated by a sigma-2 receptor. Sigma receptor antagonist, metaphit, blocked DTG-mediated inhibition of Ca2+ current. Sigma ligands also altered the biophysical properties of these channels.

Activation of sigma receptors reversibly blocked delayed outwardly rectifying potassium channels, large conductance Ca2+-sensitive K+ channels, and the M-current with maximal inhibition >80%. The rank order potency of different sigma ligands suggests that the effect is mediated by sigma-1 receptor. While bath application of sigma ligands depolarized ICG neurons, the number of action potentials (AP) fired by the cells in response to depolarizing current pulses was decreased. Experiments on the signal transduction cascade mediated the inhibition of K+ and Ca2+ channels by sigma ligands showed that the signal transduction pathway does not involve a diffusible cytosolic second messenger or a G-protein.

Sigma ligands also modulate voltage-gated Na+ channels (VGSC) in ICG neurons. Bath application of sigma ligands inhibited VGSC current with maximal inhibition >90% and altered the biophysical properties of VGSC. The latency of AP generation during depolarizing current ramp was increased by sigma ligands and this effect is through the inhibition of VGSC.

These data suggest that activation of sigma receptors on autonomic neurons modulates voltage-gated Ca2+, K+ and Na+ channels and as a result, the generation of AP is inhibited in these neurons. Sigma receptors are likely altering the cell-to-cell signaling in autonomic ganglia and thus regulating cardiac function by the peripheral nervous system.

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