A Functional Relationship between Specific NOS Isozymes and Beta-adrenergic Recep

Ohio State University, Columbus OH

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Abstract

DESCRIPTION (provided by applicant): An essential regulator of cardiac contractility is [unreadable]-adrenergic receptor ([unreadable]AR) signaling. ([unreadable]1 and [unreadable]2 receptors are the primary subtypes expressed in the heart. [unreadable]1 receptors produce positive inotropic and lusitropic effects through modulation of the L-type Ca2+ channel, phospholamban (PLB) and troponin I (Tnl). [unreadable]2 receptors are unique in that they only function as positive inotropes;these receptors promote contractility through regulation of the L-type Ca2+ channel. [unreadable]AR signaling itself can be regulated by nitric oxide (NO) produced via NO synthase (NOS). Within the myocyte, two NOS isoforms are constitutively expressed: NOS1 and NOS3. NOS1 signaling has been shown to augment the functional response to non-specific [unreadable]AR stimulation while NOS3 signaling reduces it. However, it remains to be determined what effect specific NOS isoforms have in the regulation of individual [unreadable]AR receptors. Interestingly, NOS1 and [unreadable]1 receptors have been shown to regulate contractility via similar protein targets (i.e.PLB), while NOS3 and [unreadable]2 receptors regulate contractility through the L-type Ca2+ channel. Recently, NOS3 and [unreadable]2 receptors have been shown to compartmentalize to similar locations within the myocyte. Therefore, we hypothesize NOS1 will increase the functional response due to [unreadable]1 receptor activation with no modulation of [unreadable]2 receptor signaling (Aim1). In addition, we hypothesize NOS3 will decrease the functional response due to [unreadable]2 receptor activation with no modulation of [unreadable]1 receptor signaling (Aim2). Functional experiments (i.e. measurement of Ca2+ transient, shortening amplitude, and L-type Ca2+channel current) and western blotting (PLB-phosphorylation) to investigate this proposed functional interaction will be conducted in isolated myocytes from wild type (WT, control), NOS1 knockout (KO) and NOS3 KO mice exposed to various [unreadable]AR stimuli. Our study holds health-relatedness due to the fact that when [unreadable]AR signaling is altered, this signaling pathway promotes contractile dysfunction and cardiac remodeling. Thus, it is crucial to determine how [unreadable]AR signaling is regulated. With a deeper understanding of this phenomena, our study will make possible the development of new therapeutic treatments.