Abstract
Dopamine (DA) is a well-studied neurochemical in the mammalian carotid body (CB), a chemosensory organ involved in O2 and CO2/H+ homeostasis. DA released from receptor (type I) cells during chemostimulation is predominantly inhibitory, acting via pre- and post-synaptic dopamine D2 receptors (D2R) on type I cells and afferent (petrosal) terminals respectively. By contrast, co-released ATP is excitatory at postsynaptic P2X2/3R, though paracrine P2Y2R activation of neighboring glial-like type II cells may boost further ATP release. Here, we tested the hypothesis that DA may also inhibit type II cell function. When applied alone, DA (10 μM) had negligible effects on basal [Ca2+]i in isolated rat type II cells. However, DA strongly inhibited [Ca2+]i elevations (Δ[Ca2+]i) evoked by the P2Y2R agonist UTP (100 μM), an effect opposed by the D2/3R antagonist, sulpiride (1–10 μM). As expected, acute hypercapnia (10% CO2; pH 7.4), or high K+ (30 mM) caused Δ[Ca2+]i in type I cells. However, these stimuli sometimes triggered a secondary, delayed Δ[Ca2+]i in nearby type II cells, attributable to crosstalk involving ATP-P2Y2R interactions. Interestingly sulpiride, or DA store-depletion using reserpine, potentiated both the frequency and magnitude of the secondary Δ[Ca2+]i in type II cells. In functional CB-petrosal neuron cocultures, sulpiride potentiated hypercapnia-induced Δ[Ca2+]i in type I cells, type II cells, and petrosal neurons. Moreover, stimulation of type II cells with UTP could directly evoke Δ[Ca2+]i in nearby petrosal neurons. Thus, dopaminergic inhibition of purinergic signalling in type II cells may help control the integrated sensory output of the CB during hypercapnia.
Highlights
In mammals, the main peripheral chemoreceptors are the carotid bodies (CBs), bilaterally located at the bifurcation of the common carotid artery, where they acutely monitor blood levels of O2, CO2, and pH [1,2]
It is well-established that ATP is released from type I cells during chemotransduction [5,7,30,33] and, in addition to its excitatory effects at P2X2/3R on petrosal afferent terminals [33,36,37], it may cause paracrine stimulation of P2Y2R on adjacent type II cells leading to a rise in intracellular Ca2+ and opening of ATP-permeable pannexin-1 channels [18,19,20,35]
The inhibitory effects of DA were reversibly blocked by sulpiride, an antagonist of D2 receptors that are highly expressed in the rat CB [8,10,11], suggesting that D2 receptors (D2R) may be involved
Summary
The main peripheral chemoreceptors are the carotid bodies (CBs), bilaterally located at the bifurcation of the common carotid artery, where they acutely monitor blood levels of O2, CO2, and pH [1,2]. ATP and adenosine are the best studied and these can act on both pre- and post-synaptic purinergic receptors [3,4,5,6,7]. An understanding of the physiological role of DA has been greatly aided by the numerous biochemical, pharmacological, immunohistochemical, and molecular studies characterizing both pre- and post-synaptic DA receptors in the CB of several mammalian species including humans [1,2,4,8,10,11,12]
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