Abstract
A spinal reflex and the L-arginine–nitric oxide–guanylyl cyclase–cyclic guanosine monophosphate (cGMP) pathway mediate smooth muscle relaxation that results in penile erection. Nerves and endothelial cells directly release nitric oxide in the penis, where it stimulates guanylyl cyclase to produce cGMP and lowers intracellular calcium levels. This triggers relaxation of arterial and trabecular smooth muscle, leading to arterial dilatation, venous constriction, and erection. Phosphodiesterase 5 (PDE5) is the predominant phosphodiesterase in the corpus cavernosum. The catalytic site of PDE5 normally degrades cGMP, and PDE5 inhibitors such as sildenafil potentiate endogenous increases in cGMP by inhibiting its breakdown at the catalytic site. Phosphorylation of PDE5 increases its enzymatic activity as well as the affinity of its allosteric (noncatalytic/GAF domains) sites for cGMP. Binding of cGMP to the allosteric site further stimulates enzymatic activity. Thus phosphorylation of PDE5 and binding of cGMP to the noncatalytic sites mediate negative feedback regulation of the cGMP pathway.
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References
Boolell M et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res 1996; 8: 47–52.
Boolell M, Gepi-Attee S, Gingell JC, Allen MJ . Sildenafil, a novel effective oral therapy for male erectile dysfunction. Br J Urol 1996; 78: 257–261.
Rajfer J et al. Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med 1992; 326: 90–94.
Trigo-Rocha F et al. Intracellular mechanism of penile erection in monkeys. Neurourol Urodyn 1994; 13: 71–80.
Chuang T, Strauss JD, Murphy RA, Steers WD . Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro. J Urol 1998; 160: 257–261.
Beavo JA . Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms. Physiol Rev 1995; 75: 725–748.
Fisher DA et al. Isolation and characterization of PDE8A, a novel human cAMP-specific phosphodiesterase. Biochem Biophys Res Commun 1998; 246: 570–577.
Soderling SH, Bayuga SJ, Beavo JA . Identification and characterization of a novel family of cyclic nucleotide phosphodiesterases. J Biol Chem 1998; 273: 15553–15558.
Fawcett L et al. Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. Proc Natl Acad Sci USA 2000; 97: 3702–3707.
Kuthe A et al. Expression of different phosphodiesterase genes in human cavernous smooth muscle. J Urol 2001; 165: 280–283.
Fink TL et al. Expression of an active, monomeric catalytic domain of the cGMP-binding cGMP-specific phosphodiesterase (PDE5). J Biol Chem 1999; 274: 34613–34620.
Thomas MK, Francis SH, Corbin JD . Substrate-and-kinase-directed regulation of phosphorylation of a cGMP-binding phosphodiesterase by cGMP. J Biol Chem 1990; 265: 124971–124978.
Liu L et al. Specific cGMP binding by the cGMP binding domains of cGMP-binding cGMP specific phosphodiesterase. Cell Signal 2002; 14: 45–51.
Gopal VK, Francis SH, Corbin JD . Allosteric sites of phosphodiesterase-5 (PDE5). A potential role in negative feedback regulation of cGMP signaling in corpus cavernosum. Eur J Biochem 2001; 268: 3304–3312.
Corbin JD, Turko IV, Beasley A, Francis SH . Phosphorylation of phosphodiesterase-5 by cyclic nucleotide-dependent protein kinase alters its catalytic and allosteric cGMP-binding activities. Eur J Biochem 2000; 267: 2760–2767.
Wyatt TA, Naftilan AJ, Francis SH, Corbin JD . ANF elicits phosphorylation of the cGMP phosphodiesterase in vascular smooth muscle cells. Am J Physiol 1998; 274: H448–H455.
Rybalkin SD et al. Regulation of cGMP-specific phosphodiesterase (PDE5) phosphorylation in smooth muscle cells. J Biol Chem 2002; 277: 3310–3317.
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Corbin, J. Mechanisms of action of PDE5 inhibition in erectile dysfunction. Int J Impot Res 16 (Suppl 1), S4–S7 (2004). https://doi.org/10.1038/sj.ijir.3901205
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DOI: https://doi.org/10.1038/sj.ijir.3901205
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