Frequency encoding of cholinergic- and purinergic-mediated signaling to mouse urinary bladder smooth muscle: modulation by BK channels.
In the urinary bladder, contractions of the detrusor muscle and urine voiding are induced by the neurotransmitters ACh and ATP, released from parasympathetic nerves. Activation of K(+) channels, in particular the large-conductance Ca(2+)-activated K(+) (BK) channels, opposes increases in excitability and contractility of urinary bladder smooth muscle (UBSM). We have shown that deleting the gene mSlo1 in mice (Slo(-/-)), encoding the BK channel, leads to enhanced nerve-mediated and neurotransmitter-dependent contractility of UBSM (38). Here, we examine the location of the BK channel in urinary bladder strips from mouse. Immunohistochemical analysis revealed that the channel is expressed in UBSM but not in nerves that innervate the smooth muscle. The relationship between electrical field stimulation and force generation of the cholinergic and purinergic pathways was examined by applying blockers of the respective receptors in UBSM strips from wild-type and from Slo(-/-) (knockout) mice. In wild-type strips, the stimulation frequency required to obtain a half-maximal force was significantly lower for the purinergic (7.2 +/- 0.3 Hz) than the cholinergic pathway (19.1 +/- 1.5 Hz), whereas the maximum force was similar. Blocking BK channels with iberiotoxin or ablation of the Slo gene increased cholinergic- and purinergic-mediated force at low frequencies, i.e., significantly decreased the frequency for a half-maximal force. Our results indicate that the BK channel has a very significant role in reducing both cholinergic- and purinergic-induced contractility and suggest that alterations in BK channel expression or function could contribute to pathologies such as overactive detrusor.
Werner
Matthias E
ME
Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405, USA.
Knorn
Anna-Maria
AM
Meredith
Andrea L
AL
Aldrich
Richard W
RW
Nelson
Mark T
MT
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D018678:Cholinergic Agents / Q000494:pharmacology; D004558:Electric Stimulation; D005260:Female; D007150:Immunohistochemistry; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics* / Q000502:physiology*; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000502:physiology; D009130:Muscle, Smooth / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D010275:Parasympathetic Nervous System / Q000502:physiology*; D010455:Peptides / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism; D011983:Receptors, Purinergic / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology; D001743:Urinary Bladder / Q000502:physiology*
D018678:Cholinergic Agents; C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D011976:Receptors, Muscarinic; D011983:Receptors, Purinergic; D013498:Suramin; C064719:iberiotoxin; D001285:Atropine; D000255:Adenosine Triphosphate; C002630:alpha,beta-methyleneadenosine 5'-triphosphate