HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental data All Versions of this Article: 582/3/1047    most recent jphysiol.2007.134577v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Crowder, E. A. Articles by Del Negro, C. A. Search for Related Content PubMed PubMed Citation Articles by Crowder, E. A. Articles by Del Negro, C. A. Related Collections Neuroscience

¹ Department of Applied Science, McGlothlin-Street Hall
² Department of Biology, Millington Hall, The College of William and Mary, Williamsburg, VA 23187-8795, USA
³ Department of Medicinal Chemistry, The University of Utah, 419 Wakara Way Suite 205, Salt Lake City, UT 84108, USA

Neurons of the preBötzinger complex (preBötC) form local excitatory networks and synchronously discharge bursts of action potentials during the inspiratory phase of respiratory network activity. Synaptic input periodically evokes a Ca²⁺-activated non-specific cation current (I_CAN) postsynaptically to generate 10–30 mV transient depolarizations, dubbed inspiratory drive potentials, which underlie inspiratory bursts. The molecular identity of I_CAN and its regulation by intracellular signalling mechanisms during inspiratory drive potential generation remains unknown. Here we show that mRNAs coding for two members of the transient receptor potential (TRP) family of ion channels, namely TRPM4 and TRPM5, are expressed within the preBötC region of neonatal mice. Hypothesizing that the phosphoinositides maintaining TRPM4 and TRPM5 channel sensitivity to Ca²⁺ may similarly influence I_CAN and thus regulate inspiratory drive potentials, we manipulated intracellular phosphatidylinositol 4,5-bisphosphate (PIP₂) and measured its effect on preBötC neurons in the context of ongoing respiratory-related rhythms in slice preparations. Consistent with the involvement of TRPM4 and TRPM5, excess PIP₂ augmented the inspiratory drive potential and diminution of PIP₂ reduced it; sensitivity to flufenamic acid (FFA) suggested that these effects of PIP₂ were I_CAN mediated. Inositol 1,4,5-trisphosphate (IP₃), the product of PIP₂ hydrolysis, ordinarily causes IP₃ receptor-mediated I_CAN activation. Simultaneously increasing PIP₂ while blocking IP₃ receptors intracellularly counteracted the reduction in the inspiratory drive potential that normally resulted from IP₃ receptor blockade. We propose that PIP₂ protects I_CAN from rundown by interacting directly with underlying ion channels and preventing desensitization, which may enhance the robustness of respiratory rhythm.

(Received 13 April 2007; accepted after revision 21 June 2007; first published online 28 June 2007)
Corresponding author C. A. Del Negro: Department of Applied Science, McGlothlin-Street Hall, The College of William and Mary, Williamsburg, VA 23187-8795. Email: cadeln{at}wm.edu

This article has been cited by other articles:

				C. Morgado-Valle, L. Beltran-Parrazal, M. DiFranco, J. L. Vergara, and J. L. Feldman Somatic Ca2+ transients do not contribute to inspiratory drive in preBotzinger Complex neurons J. Physiol., September 15, 2008; 586(18): 4531 - 4540. [Abstract] [Full Text] [PDF]

				C. A. Del Negro and J. A. Hayes A 'group pacemaker' mechanism for respiratory rhythm generation J. Physiol., May 1, 2008; 586(9): 2245 - 2246. [Full Text] [PDF]

				S. L. Mironov Metabotropic glutamate receptors activate dendritic calcium waves and TRPM channels which drive rhythmic respiratory patterns in mice J. Physiol., May 1, 2008; 586(9): 2277 - 2291. [Abstract] [Full Text] [PDF]

				B. Robertson Regulation of ion channels and transporters by phosphatidylinositol 4,5-bisphosphate J. Physiol., August 1, 2007; 582(3): 901 - 902. [Full Text] [PDF]