Respiratory responses to hypercapnia and hypoxia in mice with genetic ablation of Kir5.1 (Kcnj16).
Inward rectifier (Kir) potassium channels contribute to the control of electrical activity in excitable tissues and their activity is modulated by many biochemical factors, including protons. Heteromeric Kir4.1-Kir5.1 channels are highly pH sensitive within the physiological range of pH changes and are strongly expressed by the peripheral chemosensors as well as in the brainstem pH-sensitive areas which mediate respiratory responses to changes in blood and brain levels of P(CO(2))/[H(+)]. In the present study, Kir5.1 knockout mice (Kir5.1(-/-)) were used to determine the role of these channels in the chemosensory control of breathing. We found that Kir5.1(-/-) mice presented with persistent metabolic acidosis and a clear respiratory phenotype. Despite metabolic acidosis, ventilation at rest and in hyperoxic hypercapnia were similar in wild-type and Kir5.1(-/-) mice. Ventilatory responses to hypoxia and normoxic hypercapnia were significantly reduced in Kir5.1(-/-) mice; however, carotid body chemoafferent responses to hypoxia and CO(2) were not affected. In the in situ brainstem-spinal cord preparations with denervated peripheral chemoreceptors, resting phrenic nerve activity and phrenic nerve responses to respiratory acidosis or isohydric hypercapnia were also similar in Kir5.1(-/-) and wild-type mice. In in situ preparations of Kir5.1(-/-) mice with intact peripheral chemoreceptors, application of CN(-) resulted in a significantly reduced phrenic nerve response, suggesting that the relay of peripheral chemosensory information to the CNS is compromised. We suggest that this compensatory modulation of the peripheral chemosensory inputs develops in Kir5.1(-/-) mice in order to counteract the effect of continuing metabolic acidosis on the activity of the peripheral chemoreceptors. These results therefore suggest that despite their intrinsic pH sensitivity, Kir4.1-Kir5.1 channels are dispensable for functional central and peripheral respiratory chemosensitivity.
Department of Surgery and Cancer, Biophysics Section, Imperial College London, London, UK.
Stefan
S
Trapp
Stephen J
SJ
Tucker
Alexander V
AV
Gourine
D000138:Acidosis / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D001933:Brain Stem / Q000378:metabolism / Q000503:physiopathology; D002245:Carbon Dioxide / Q000378:metabolism; D002344:Carotid Body / Q000378:metabolism / Q000503:physiopathology; D006863:Hydrogen-Ion Concentration; D006935:Hypercapnia / Q000235:genetics / Q000503:physiopathology*; D000860:Hypoxia / Q000235:genetics / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010791:Phrenic Nerve / Q000378:metabolism / Q000503:physiopathology; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012137:Respiratory System / Q000503:physiopathology*; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology; D000097062:Kir5.1 Channel
D001639:Bicarbonates; D002245:Carbon Dioxide; D024661:Potassium Channels, Inwardly Rectifying; D000097062:Kir5.1 Channel
J Neurophysiol. 2010 Dec;104(6):3042-52
20926613
J Physiol. 1999 May 1;516 ( Pt 3):699-710
10200419
J Neurosci. 2003 Dec 10;23(36):11315-21
14672995
Am J Physiol Cell Physiol. 2010 Mar;298(3):C635-46
20042730
J Neurosci. 2000 Aug 1;20(15):5733-40
10908613
J Physiol. 2001 Apr 15;532(Pt 2):359-67
11306656
J Physiol. 2002 Jan 15;538(Pt 2):391-404
11790808
Proc Natl Acad Sci U S A. 2004 May 25;101(21):8215-20
15141089
J Vet Med Sci. 2008 Mar;70(3):265-71
18388426
Recept Channels. 1994;2(3):183-91
7874445
J Neurosci Methods. 1996 Mar;65(1):63-8
8815310
Science. 2010 Jul 30;329(5991):571-5
20647426
EMBO J. 1996 Aug 15;15(16):4093-9
8861938
J Neurosci. 2007 Dec 19;27(51):14049-58
18094244
J Physiol. 2000 May 1;524 Pt 3:725-35
10790154
Physiol Rev. 2010 Jan;90(1):291-366
20086079
J Membr Biol. 2004 Feb 1;197(3):179-91
15042349
Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2325-30
20133877
J Biol Chem. 2000 Jun 2;275(22):16404-7
10764726
EMBO J. 1996 Jun 17;15(12):2980-7
8670799
Am J Physiol Renal Physiol. 2008 Jun;294(6):F1398-407
18367659
J Physiol. 1999 Feb 1;514 ( Pt 3):639-53
9882736
J Neurosci. 2008 Aug 27;28(35):8844-50
18753386
Nat Neurosci. 2004 Dec;7(12):1360-9
15558061
J Appl Physiol (1985). 2009 Apr;106(4):1464-6
18467549
J Biol Chem. 2011 Jan 7;286(1):192-8
21047793
Respir Physiol. 2001 Dec;129(1-2):141-57
11738651
Respir Physiol. 1979 Aug;37(3):365-79
493756
Histol Histopathol. 2008 Jul;23(7):799-806
18437678