Stimulation of 5-HT₂ receptors in prefrontal pyramidal neurons inhibits Ca_v1.2 L-type Ca²⁺ currents via a PLCβ/IP3/calcineurin signaling cascade

There is growing evidence linking alterations in serotonergic signaling in the prefrontal cortex to the etiology of schizophrenia. Prefrontal pyramidal neurons are richly innervated by serotonergic fibers and express high levels of serotonergic 5-HT₂-class receptors. It is unclear, however, how activation of these receptors modulates cellular activity. To help fill this gap, whole cell voltage-clamp and single-cell RT-PCR studies of acutely isolated layer V-VI prefrontal pyramidal neurons were undertaken. The vast majority (>80%) of these neurons had detectable levels of 5-HT_2A or 5-HT_2C receptor mRNA. Bath application of 5-HT₂ agonists inhibited voltage-dependent Ca²⁺ channel currents. L-type Ca²⁺ channels were a particularly prominent target of this signaling pathway. The L-type channel modulation was blocked by disruption of G_αq signaling or by inhibition of phospholipase Cβ. Antagonism of intracellular inositol trisphosphate signaling, chelation of intracellular Ca²⁺, or depletion of intracellular Ca²⁺ stores also blocked this modulation. Inhibition of the Ca²⁺-dependent phosphatase calcineurin prevented receptor-mediated modulation of L-type currents. Last, the 5-HT₂ receptor modulation vas robustly expressed in neurons from Ca_v1.3 knockout mice. These findings argue that 5-HT₂ receptors couple through G_αq proteins to trigger a phospholipase Cβ/inositol trisphosphate signaling cascade resulting in the mobilization of intracellular Ca²⁺, activation of calcineurin, and inhibition of Ca_v1.2 L-type Ca²⁺ currents. This modulation and its blockade by atypical neuroleptics could have wide-ranging effects on synaptic integration and long-term gene expression in deep-layer prefrontal pyramidal neurons.