This article was downloaded by: [] On: 01 November 2014, At: 14:13 Publisher: Taylor & Francis Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK Channels Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/kchl20 Ion channels of the mammalian urethra Barry D Kyle a a Department of Physiology & Pharmacology; Libin Cardiov
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  This article was downloaded by: []On: 01 November 2014, At: 14:13Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,37-41 Mortimer Street, London W1T 3JH, UK Channels Publication details, including instructions for authors and subscription information:http://www.tandfonline.com/loi/kchl20 Ion channels of the mammalian urethra Barry D Kyle aa  Department of Physiology & Pharmacology; Libin Cardiovascular Institute and The SmoothMuscle Research Group; University of Calgary; Calgary, AB CanadaAccepted author version posted online: 31 Oct 2014. To cite this article:  Barry D Kyle (2014) Ion channels of the mammalian urethra, Channels, 8:5, 393-401, DOI:10.4161/19336950.2014.954224 To link to this article: http://dx.doi.org/10.4161/19336950.2014.954224 PLEASE SCROLL DOWN FOR ARTICLETaylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained inthe publications on our platform. Taylor & Francis, our agents, and our licensors make no representations orwarranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Versionsof published Taylor & Francis and Routledge Open articles and Taylor & Francis and Routledge Open Selectarticles posted to institutional or subject repositories or any other third-party website are without warrantyfrom Taylor & Francis of any kind, either expressed or implied, including, but not limited to, warranties of merchantability, fitness for a particular purpose, or non-infringement. Any opinions and views expressed in thisarticle are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. Theaccuracy of the Content should not be relied upon and should be independently verified with primary sourcesof information. Taylor & Francis shall not be liable for any losses, actions, claims, proceedings, demands,costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly inconnection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Terms & Conditions of access anduse can be found at http://www.tandfonline.com/page/terms-and-conditions  It is essential that you check the license status of any given Open and Open Select article to confirmconditions of access and use.  Ion channels of the mammalian urethra Barry D Kyle* Department of Physiology & Pharmacology; Libin Cardiovascular Institute and The Smooth Muscle Research Group; University of Calgary; Calgary, AB Canada Keywords:  electrophysiology, ion channels, myogenic tone, patch clamp, smooth muscle, urethra, urethral innervation  The mammalian urethra is a muscular tube responsible forensuring that urine remains in the urinary bladder untilurination. In order to prevent involuntary urine leakage, theurethral musculature must be capable of constricting theurethral lumen to an extent that exceeds bladderintravesicular pressure during the urine- 󿬁 lling phase. Themain challenge in anti-incontinence treatments involvesselectively-controlling the excitability of the smooth musclesin the lower urinary tract. Almost all strategies to battleurinary incontinence involve targeting the bladder and as aresult, this tissue has been the focus for the majority of research and development efforts. There is now increasingrecognition of the value of targeting the urethral musculaturein the treatment and management of urinary incontinence.Newly-identi 󿬁 ed and characterized ion channels andpathways in the smooth muscle of the urethra provides arange of potential therapeutic targets for the treatment of urinary incontinence. This review provides a summary of thecurrent state of knowledge of the ion channels discovered inurethral smooth muscle cells that regulate their excitability. Role of the Urethra in the Lower Urinary Tract The filtration of blood by glomeruli in the kidney leads to theformation of urine, which is then transported to the urinary blad-der by specialized muscular tubes called ureters that undergofinely-tuned peristaltic waves to prevent urine backflow towardthe kidneys. 1,2 The bladder is a hollow muscular organ capableof receiving and storing urine as it is propelled by the ureters intoits interior. The compliant bladder expands as urine fills its inte-rior and raises intravesicular pressure on the bladder walls. Theimpulse/desire to urinate is thought to result from the high firing rate of afferent sensory nerves stimulated by mechanoreceptors inthe bladder wall, which are activated by the rise in intravesicularpressure in the bladder. 3,4 These afferent sensory nerves projecttop the dorsal horn of the spinal cord via the pelvic nerve andconnecting fibers then travel to higher brain regions (i.e., pontinemicturition center and cerebrum 5 ). The urethra is located distalto the bladder neck and connects the bladder interior to the exte-rior environment ( Fig. 1 ). It is a structurally-complex multi-lay-ered tissue comprising the lamina propria, including bothmucosa and submucosa, as well as longitudinal and circular layersof smooth muscle. 6 The urethra also contains striated muscleproximal to the pelvic floor, often referred to as the external ure-thral sphincter. 7 Contraction of this muscle is commonly associ-ated with the “guarding reflex” experienced during times of highbladder intravesicular pressure (e.g., sneezing, coughing). 8-11 Theadult female urethra is embedded in the anterior vaginal wall andtypically ranges 3-4 cm in length and » 0.6 cm in luminal diam-eter. 12,13  Although the male urethra is  » 20 cm in length, it ismainly the prostatic and pre-prostatic regions ( Fig. 1 ) that con-tribute to the true internal urethral sphincter. 6,14 In healthy individuals, the process of urination is a coordi-nated voiding mechanism involving the contraction of the detru-sor muscle lining the bladder, combined with the relaxation of the urethral smooth muscle, also known as the internal urethralsphincter ( Fig. 1 ). During the urine filling/storage phase, urineoutflow from the bladder does not occur by virtue of the fact thatthe bladder musculature is largely relaxed and electrically quies-cent, while the urethra, a conduit muscular tube extending fromthe base of the bladder, maintains a constant tone and is effec-tively closed (excellent reviews are available describing bladderand urethral physiology/pharmacology). 6,13 Early studies utiliz-ing catheters in humans reported a time-delay ranging from 5-15seconds between the relaxation of urethral musculature and con-traction of the bladder detrusor muscle. 15-18 It is well-established that the inability of the urethral muscula-ture to maintain sufficient tone can result in involuntary urineleakage. 6,19-21 Damage to urethral smooth musculature may bein the form of acute trauma (e.g., surgical intervention, childbirthcomplications) 19,20,22,23 or from aging-related diseases. 13,22,23 Recently there has been an increasing recognition of the value of targeting the urethral musculature in the clinical management of urinary incontinence. The array of ion channels located in ure-thral smooth muscle membranes play a crucial role in determin-ing internal urethral sphincter excitability and therefore theoverall function of the urethra. 6,24 Studying electrical activity in the urethra  The mammalian urethra is known to exhibit spontaneousmechanical activity, but during the urine-storage phase, muscleactivity is mostly tonic in nature. 6 The complex nature of ure-thral tissue has presented many challenges in studying its func-tion in detail. Most current knowledge regarding the role of ionchannels in the urethra has come from isometric tension © Barry D Kyle*Correspondence to: Barry D Kyle; Email: BDKyle@ucalgary.caSubmitted: 04/29/2014; Revised: 08/05/2014; Accepted: 08/06/2014http://dx.doi.org/10.4161/19336950.2014.954224 This is an Open Access article distributed under the terms of the CreativeCommons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use,distribution, and reproduction in any medium, provided the srcinal work isproperly cited. The moral rights of the named author(s) have been asserted. www.landesbioscience.com 393ChannelsChannels 8:5, 393--401; September/October 2014; Published with license by Taylor & Francis Group, LLC REVIEW    D  o  w  n   l  o  a   d  e   d   b  y   [   7   0 .   7   2 .   1   9   1 .   2   2   0   ]  a   t   1   4  :   1   3   0   1   N  o  v  e  m   b  e  r   2   0   1   4  recordings, 25-31 sharp microelectrode recordings of intact prepa-rations,  25,27,32,33 and the patch clamp technique. 29-31,33-40 Earlier studies measuring electrical and mechanical (i.e., force)activity in rabbit urethral smooth muscle reported that the spon-taneous activity was in fact myogenic in nature, 25,41 resembling the activity seen in the GI tract. 42 Thus, the excitability appeared to be driven by a form of pacemaker originating within the muscle itself. It is important to apply caution wheninterpreting data from intact preparations, such as from tensionand microelectrode recordings, since (i) the urethral smoothmusculature contains a mixed population of cells that includes a range of non-contractile interstitial cells of Cajal (ICC)-like cells( Fig. 1B , see focused reviews), 43,44 and (ii) the urethra receivesinnervation from sympathetic and parasympathetic nervous sys-tems. 25,28,29,31 It is extremely difficult, therefore, to reliably iso-late the role of ion channels in a given cell type using suchintact preparations, particularly with limited pharmacology. Thepatch clamp technique, 45 on the other hand, remains the only reliable method currently available to study the behavioral prop-erties of ion channels expressed on the surface membranes of the ICCs and smooth muscle cells of the urethra. Recent advan-ces in isolating toxins and selective pharmacological agents havegreatly aided in identifying and profiling the roles of ion chan-nels, as discussed below. K  C Channels in Urethral Smooth Muscle Cells The Brading research group successfully applied the patchclamp technique to urethral smooth muscle cells isolated frompigs in the late 1990s, reporting a number of different K  C channel currents 34,35,46 that exhibited small and large conduc-tance properties. One conductance in particular showed char-acteristics consistent with ATP-sensitive K  C (K   ATP ) channels,and was the focus of the early studies principally using the pig model. K   ATP  channels K   ATP  channels are formed by the combination of 4 inwardly-rectifying K  C (K  ir ) channel subunits, comprising the pore-form-ing core, surrounded by a ring of 4 regulatory sulfonylurea subu-nits ( Fig. 2  and review). 47 The K   ATP  channels identified in theurethral smooth muscle cells have a single channel conductanceof 43 pS and their activation by pharmacologic agents wasreported to hyperpolarize the membrane potential. Thus, K  C efflux from these channels drives the membrane potential in thenegative direction, decreasing excitability. Since then, K  ir 6.1 andK  ir 6.2 subunit transcripts have been detected and it has been sug-gested that the K   ATP  channel comprises a “mixed” (i.e. heterote-trameric) channel of K  ir 6.1 and K  ir 6.2 subunits, since theobserved conductance value of 43 pS was intermediate betweenthose measured for homomeric channels consisting of eitherK  ir 6.1 or 6.2 subunits. 47-50 It has recently been definitively reported that the pore-forming region of the urethral smoothmuscle K   ATP  channel is in fact a heterotetrameric complex of K  ir 6.1 and K  ir 6.2 subunits, arranged in a 3:1 ratio ( Fig. 2 ). 38 Inaddition, transcripts for the regulatory sulfonylurea receptorsSUR1 and SUR2B have also been detected, and are known tofunctionally co-assemble. 50,51 Figure 1.  ( A ) A representation of the anatomy of the lower urinary tract including bladder and urethral structures, with inputs from various nervous sys-tems illustrated. ( B ) A smooth muscle bundle depicting smooth muscle cells in close contact with an ICC-like cell and nerve. Abbreviations: ACh, acetyl-choline; NO, nitric oxide; ATP, adenosine 5 0 -triphosphate; ICC, interstitial cell of Cajal.394 Volume 8 Issue 5Channels    D  o  w  n   l  o  a   d  e   d   b  y   [   7   0 .   7   2 .   1   9   1 .   2   2   0   ]  a   t   1   4  :   1   3   0   1   N  o  v  e  m   b  e  r   2   0   1   4  Thorough studies by Teramotoand colleagues outlining the bio-physical properties of K   ATP  channelsin the pig urethra has provided valu-able experimental evidence thatK   ATP  channels contribute to setting the resting membrane potential ( »¡ 37 mV). 38,46 Important physio-logical implications result from theparticular heterotetrameric arrange-ment of the channel complex identi-fied in the urethra that distinguish itfrom other smooth muscle typessuch as those found in vascular tis-sues. 52,53 The gating properties (i.e.,activation) of the heterotetramericK   ATP  channel complex found in theurethra can be dynamically modu-lated by protein kinase C (PKC), 38 which is distinct from the mecha-nism observed in vascular smoothmuscle for K   ATP  channels. 53  Voltage and Ca  2 C -activated K  C channels Following elucidation of the role of K   ATP  channels in urethral smoothmuscle cells, the next series of break-throughs in characterizing urethralsmooth muscle cell ion channel prop-erties srcinated from a collaborationamong the Hollywood, McHale andThornbury laboratories investigating K  C channels and voltage-gated Ca  2 C channels (VGCCs,  Fig. 2 ). Urethralsmooth muscle cells were reported tohave large conductance, Ca  2 C -acti-vated K  C (BK  Ca  ) channels and volt-age-gated K  C (K  v  ) channels carrying outwardly-rectifying K  C current( Fig.3 ). 40 HoweverthelackofK  v  -spe-cific inhibitors/enhancers at that timehampered further identification andprofiling of the K  v   conductances. Thesubsequent isolation and developmentof toxins, such as the tarantula spidervenom peptide, stromatoxin 1(ScTx), 54,55 has provided a valuableselective pharmacological tool to study certain K  v   channels. ScTx targets thevoltage sensor domain in homotetra-meric K  v   channels K  v  2.1, K  v  2.2 andK  v  4.2. 30,54 In addition, ScTx has beenshown to inhibit heterotetramericK  v  2.1/6.3 56 and K  v  2.1/9.3-containing K  v   channels. 30,54,57,58 Using the ScTx  Figure 2.  A schematic illustration of the various ion channels identi 󿬁 ed in urethral smooth muscle. Thearchitecture of the transmembrane  a  and  b  subunits is shown in the left panel. Dimeric and trimericarrangements can be seen for K  2P  and P2X channels, respectively. Most channels have tetrameric struc-tures and several have  b  subunits associated. Abbreviations: N, amino-terminus; C, carboxyl-terminus; K  ir ,inwardly-rectifying K  C channel; SUR, sulfonylurea; TMD, transmembrane domain; K  ATP , ATP-sensitive K  C channel; C , positively-charged residues; BK  Ca , large conductance, Ca 2 C -activated K  C channel; K  v , voltage-gated K  C channel; CaM, calmodulin; K2P, 2-pore domain K  C channel; IK  Ca , intermediate conductance K  C channel; SK  Ca , small conductance K  C channel; VGCC, voltage-gated Ca 2 C channel; CaCC, Ca 2 C -activatedCl ¡ channel.www.landesbioscience.com 395Channels    D  o  w  n   l  o  a   d  e   d   b  y   [   7   0 .   7   2 .   1   9   1 .   2   2   0   ]  a   t   1   4  :   1   3   0   1   N  o  v  e  m   b  e  r   2   0   1   4
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