NICOTINIC RECEPTORS IN MAMMALIAN INTRACARDIAC NEURONS

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The mammalian parasympathetic intracardiac ganglia mediate autonomic regulation of the heart. All parasympathetic and some sympathetic input to the heart, as well as afferent output, is provided by neurons within cardiac ganglia. Previous studies have revealed a morphological and neurochemical complexity which suggests that the cardiac ganglia may serve an integrative function, facilitating local feedback and autoregulation. Acetylcholine (ACh) is the primary neurotransmitter mediating intrinsic and extrinsic innervation of the ganglia, and fast excitatory transmission is provided by nicotinic ACh receptors- channels (AChRs). Recent experiments indicate that multiple subtypes of AChRs are expressed by individual rat intracardiac neuron, and the majority express the alpha7 subunit gene. Alpha7- AChRs are known to bind alpha-bungarotoxin (alpha Bgt), are highly permeable to Ca2+, and serve a variety of physiological functions. Preliminary results have shown for the first time alpha Bgt-sensitive ACh responses in rat intracardiac neurons and the first evidence for alpha7-AChR-mediated currents in mammalian peripheral neurons. Surprisingly, rat intracardiac neuron alpha7- AChRs slowly desensitize and rapidly recover from alpha- bungarotoxin blockade, properties significantly different from those reported for this AChR subtype in other neurons. Insight into the circuitry of the cardiac ganglia will be gained by characterizing a key element of ganglionic synaptic transmission, alpha7-AChRs. To achieve this primary objective, this proposal aims to: 1. Identify the distinctive pharmacological and electrical properties, such as Ca2+ permeability, of alpha7-AChRs in isolated rat intracardiac neurons. 2. Investigate mechanisms, such as co-assembly with other AChR subunits and regulation by intracellular second messengers, that may underlie the distinct properties of alpha7-AChRs. 3. Determine the physiological role of alpha7-AChRs in cell-cell signaling in the cardiac ganglion, including ability to elevate intracellular Ca2+ and effects on action potential firing. 4. Investigate the modulation of alpha7-AChRs by neuropeptides shown to alter the properties of AChRs. A multifaceted approach involving patch-clamp electrophysiology, immunohistochemistry, and molecular biology will be used. alpha7-AChRs are likely to play a major role in cell-cell signaling in intracardiac ganglia and therefore in the regulation of heart rate, cardiac contractility, and/or coronary vascular tone. An understanding of the properties and physiological role of the receptors is necessary to comprehend neural control of the heart.