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KIR CHANNEL MODULATIONS IN HYPERCAPNIC ACIDOSIS

Award Number: R01HL058410
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/1996
PERIOD OF PERFORMANCE END DATE: 02/28/2005

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KIR CHANNEL MODULATIONS IN HYPERCAPNIC ACIDOSIS - DESCRIPTION (Applicant's abstract): As an early event in CO2 sensing, changes in membrane excitability have been demonstrated in brainstem CO2 chemo sensitive neurons, which seem to result from alternations in synaptic transmission, transporter activity and/or ion channel activation. Indeed, studies including ours have shown that K+ channels are the key players in controlling membrane excitability in these chemo sensitive neurons. We have found that the hypercapnia-induced depolarization is attenuated by antagonism of K+ channels, while blockade of synaptic transmission and several other ion channels has no effect. We have thereafter studied these CO2-sensitive K+ channels and demonstrated a novel CO2 sensing mechanism in these channels. This mechanism relies on the inherent pH-sensing and channel-gating processes of inward rectifier K+ channels, allowing the change in PCO2 levels to be coupled to a nonexpanding change in membrane excitability. Among these CO2-sensitive K+ channels, the heteromeric Kir4.1-Kir5.1 is particularly interesting. With a linear working range at physiologic pH levels, these channels can detect both hypercapnia and hypocapnia. These plus their brainstem-specific expression make them the highly promising candidates for the potential CO2 sensing molecules in the central CO2 chemoreceptors. Clearly, detailed studies of the molecular mechanisms underlying the CO2 sensing in these K+ channels may yield important information of CO2 chemoreception. Thus, we have proposed experiments to test three specific hypotheses: 1) the heteromeric Kir4.1 -Kir5.1 channels act as CO2 sensors 2) the Kir4.1 -Kir5.1 channels are specifically expressed in brainstem neurons; and 3) CO2 enhances membrane excitability of chemo sensitive neurons by inhibiting the Kir4.1 -Kir5.1 channels. The outcome of these studies will not only improve our understanding of CO2 chemo receptive physiology but also may help the design of medical interventions by manipulating these cellular inherent CO2-sensing and responding mechanisms in the treatment and prevention of certain illnesses that are related to the CO2 sensation and modulation in central and peripheral cells.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2004 ( Subtotal = $285,793 )
2004	2004	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Lung Diseases Research	000	8	3/17/2004	NON-COMPETING CONTINUATION	$285,793
														Subtotal = $285,793

Issue Date FY: 2003 ( Subtotal = $249,132 )
2003	2003	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Lung Diseases Research	000	7		NON-COMPETING CONTINUATION	$249,132
														Subtotal = $249,132

Issue Date FY: 2002 ( Subtotal = $248,248 )
2002	2002	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Lung Diseases Research	000	6	3/1/2002	NON-COMPETING CONTINUATION	$248,248
														Subtotal = $248,248

Issue Date FY: 2001 ( Subtotal = $247,390 )
2001	2001	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Lung Diseases Research	000	5	3/9/2001	COMPETING CONTINUATION	$214,500
2001	2001	GEORGIA STATE UNIVERSITY RESEARCH FOUNDATION	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Lung Diseases Research	001	5	8/17/2001	SUPPLEMENT FOR EXPANSION	$32,890
														Subtotal = $247,390

Issue Date FY: 1999 ( Subtotal = $210,707 )
1999	1999	GEORGIA STATE UNIVERSITY	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Lung Diseases Research	000	4	8/16/1999	NON-COMPETING CONTINUATION	$210,707
														Subtotal = $210,707

Issue Date FY: 1998 ( Subtotal = $202,599 )
1998	1998	GEORGIA STATE UNIVERSITY	PO BOX 4030	ATLANTA	GA	30302	FULTON	USA	Lung Diseases Research	000	3	8/6/1998	NON-COMPETING CONTINUATION	$202,599
														Subtotal = $202,599

Grand Total All Awards = $1,443,869

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KIR CHANNEL MODULATIONS IN HYPERCAPNIC ACIDOSIS

Award Number: R01HL058410

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/1996

PERIOD OF PERFORMANCE END DATE: 02/28/2005

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