Stimulation of serotonin transport by the cyclic GMP phosphodiesterase-5 inhibitor sildenafil.

Zhu CB, Hewlett WA, Francis SH, Corbin JD, Blakely RD
Eur J Pharmacol. 2004 504 (1-2): 1-6

PMID: 15507214 · DOI:10.1016/j.ejphar.2004.09.023

The serotonin (5-hydroxtryptamine, 5-HT) transporter (SERT) plays a critical role in the inactivation of synaptic 5-HT and has been implicated in multiple psychiatric and peripheral disorders. SERT regulation studies demonstrate that activation of cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG)-linked pathways can increase SERT activity. As cGMP actions are limited by cGMP-specific phosphodiesterase (PDEs), we investigated whether the cGMP-specific PDE5 inhibitor sildenafil (Viagra) can stimulate 5-HT uptake and potentiate cGMP-mediated regulation. In RBL-2H3 cells, SERT activity was stimulated by sildenafil in a concentration- and time-dependent manner. Sildenafil also enhanced the stimulation of SERT triggered by the adenosine receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), effects blocked by the PKG inhibitor N-[2-(methylamino)ethy]-5-isoquinoline-sulfonamide (H8). Sildenafil stimulation of 5-HT uptake arises from an increase in 5-HT transport Vmax and is paralleled by elevated SERT surface antagonist binding, also H8-sensitive. These findings implicate cGMP-targeted PDEs in limiting the regulation of antidepressant-sensitive 5-HT transport.

MeSH Terms (17)

3',5'-Cyclic-GMP Phosphodiesterases Animals CHO Cells Cricetinae Cyclic Nucleotide Phosphodiesterases, Type 5 Membrane Glycoproteins Membrane Transport Proteins Nerve Tissue Proteins Phosphodiesterase Inhibitors Piperazines Protein Binding Purines Rats Serotonin Serotonin Plasma Membrane Transport Proteins Sildenafil Citrate Sulfones

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