Erectile dysfunction in mice lacking the large-conductance calcium-activated potassium (BK) channel.
Penile erection is dependent on the nitric oxide (NO)/cGMP-dependent protein kinase I (PKGI) pathway. One important target of PKGI in smooth muscle is the large-conductance, calcium-activated potassium (BK) channel, which upon activation hyperpolarizes the smooth muscle cell membrane, causing relaxation. Relaxation of arterial and corpus cavernosum smooth muscle (CCSM) is necessary to increase blood flow into the corpora cavernosa that leads to penile tumescence. We investigated the functional role of BK channels in the corpus cavernosum utilizing a knock-out mouse lacking the Slo gene (Slo-/-) responsible for the pore-forming subunit of the BK channel. Whole-cell currents were recorded from isolated CCSM cells of Slo+/+ and Slo-/- mice. Iberiotoxin-sensitive voltage- and [Ca2+]-activated K+ currents, the latter activated by local transient calcium releases (calcium sparks), were present in Slo+/+ CCSM cells, but absent in Slo-/- cells. CCSM strips from Slo-/- mice demonstrated a four-fold increase in phasic contractions, in the presence of phenylephrine. Nerve-evoked relaxations of precontracted strips were reduced by 50%, both in strips from Slo-/- mice and by blocking BK channels with iberiotoxin in the Slo+/+ strips. Consistent with the in vitro results, in vivo intracavernous pressure exhibited pronounced oscillations in Slo-/- mice, but not in Slo+/+ mice. Furthermore, intracavernous pressure increases to nerve stimulation, in vivo, were reduced by 22% in Slo-/- mice. These results indicate that the BK channel has an important role in erectile function, and loss of the BK channel leads to erectile dysfunction.
Werner
Matthias E
ME
Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405, USA.
Zvara
Peter
P
Meredith
Andrea L
AL
Aldrich
Richard W
RW
Nelson
Mark T
MT
D000818:Animals; D007172:Erectile Dysfunction / Q000235:genetics / Q000503:physiopathology*; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000503:physiopathology*; D010410:Penile Erection; D010413:Penis / Q000503:physiopathology*; D024681:Potassium Channels, Calcium-Activated / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D051036:Large-Conductance Calcium-Activated Potassium Channels; D024681:Potassium Channels, Calcium-Activated