Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice.
The generation of nitric oxide (NO) in penile erectile tissue and the subsequent elevation of cyclic GMP (cGMP) levels are important for normal penile erection. Current treatments of erectile dysfunction elevate either cGMP levels by blocking cGMP degrading phosphodiesterase 5 or cyclic AMP (cAMP) levels by intrapenile injection of prostaglandin E1. The molecular target or targets of cGMP in erectile tissue and the role of cAMP for normal penile erection are not known. Herein, we report that mice lacking cGMP-dependent kinase I (cGKI) have a very low ability to reproduce and that their corpora cavernosa fail to relax on activation of the NO/cGMP signaling cascade. Elevation of cAMP by forskolin, however, induces similar relaxation in normal and cGKI-null corpus cavernosum. In addition, sperm derived from cGKI-null mice is normal, can undergo acrosomal reactions, and can efficiently fertilize eggs. Altogether, these data identify cGKI as the downstream target of cGMP in erectile tissue and provide evidence that cAMP signaling cannot compensate for the absence of the cGMP/cGKI signaling cascade in vivo.
Hedlund
P
P
Department of Clinical Pharmacology, University of Lund, S-221 85 Lund, Sweden.
Aszodi
A
A
Pfeifer
A
A
Alm
P
P
Hofmann
F
F
Ahmad
M
M
Fassler
R
R
Andersson
K E
KE
D000818:Animals; D002352:Carrier Proteins / Q000032:analysis; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism* / Q000502:physiology; D007172:Erectile Dysfunction / Q000201:enzymology*; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D019001:Nitric Oxide Synthase / Q000032:analysis; D052248:Nitric Oxide Synthase Type I; D010410:Penile Erection / Q000502:physiology*; D010413:Penis; D013869:Thiolester Hydrolases / Q000032:analysis; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis; D043222:Ubiquitin Thiolesterase; D014660:Vasoactive Intestinal Peptide / Q000032:analysis; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins
D002352:Carrier Proteins; D026901:Membrane Transport Proteins; C493459:SLC18A3 protein, human; C493460:Slc18a3 protein, mouse; D050494:Vesicular Acetylcholine Transport Proteins; D033921:Vesicular Transport Proteins; D014660:Vasoactive Intestinal Peptide; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D014446:Tyrosine 3-Monooxygenase; D017869:Cyclic GMP-Dependent Protein Kinases; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase