Modulation of Voltage-gated K Channels in Glomus Cells

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DESCRIPTION (provided by applicant): Systemic hypoxia is a potentially lethal situation for the animal. To protect major organs from irreversible damage, the carotid body, a primary arterial chemosensory organ, sends a message to the brain and induces various systemic responses. The mechanisms of hypoxic chemotransmission in the carotid body is not still clear, but the involvement of K+ channels and neurotransmitters has been indicated. Studies have shown that acetylcholine (ACh) plays an active role in the excitation of glomus cells. Accordingly, we hypothesized that interaction between ACh and voltage-gated K+ (Kv) channels plays an important role in the excitation of glomus cells. Our preliminary studies showed that low doses of ACh enhanced and high doses of ACh inhibited Kv current in cat glomus cells. We will extend these studies and investigate mechanisms involved in the modulation of Kv channels by ACh. Patch clamp, microfluorometric, gene expression array, RT-PCR and immunocytochemical techniques will be applied. Initially we will use our cat model, because we have already characterized Kv channels and cholinergic receptors in cat glomus cells. Contribution of nicotinic, muscarinic M1 and M2 receptors to the modulation of Kv current in relation to cytosolic Ca2+, PKC and tyrosine kinase will be investigated. These studies will reveal how the interaction between ACh and Kv channels occurs at subcellular level (Specific Aim 1). Subsequently, we will extend our studies to a mouse model (DBA/2J and A/J strains). Hypoxic ventilatory responses and glomus cell responses to ACh in these strains are substantially different. We have hypothesized that variations in cholinergic modulation of Kv channels are the bases of these differences (Specific aim 2). The studies in mice will show whether these differences are genetically controlled. The proposed studies will give new insight into mechanisms of the carotid body excitation. In the perspective of public health, understanding the chemosensory and chemotransductive mechanisms may be valuable for the treatment of some pathological conditions related to carotid body function such as primary hypertension, obstructive sleep apnea, abnormal ventilation in Prader-Willi syndrome, sudden infant death syndrome and congenital central hypoventilation syndrome. These diseases are known to have a genetic basis.