Ganglionic-type nicotinic receptor

The calcium permeability of ganglion-type nicotinic receptors is reported to be similar to that of adult muscle in experiments on superior cervical ganglion, intracardiac ganglia, and chromaffin cells, with values for calcium permeability (relative to sodium or cesium) between 0.5 and 1 and fractional current mea-... 

In other instances such apparent hybrid activities could be missing or less prominent, as shows the example of epibatidine, a powerful alkaloid from the skin of several arrow poison frogs. Synthetic (+)- and natural (-)-epibatidine have potent agonist activity at ganglionic-type nicotinic receptors. The epibatidines have little or no activity at a variety of other central receptors, including opioid receptors, muscarinic receptors, adrenergic receptors, dopamine receptors, serotonin receptors, and GABA receptors [81]. 

There is indeed evidence that subunit combinations even more complex than the ones outlined above do form in native neurons (the list that follows is by no means exhaustive). For instance, immunoprecipitation showed that a fraction of the major type of nicotinic receptor in ciliary ganglion neurons (ac3/34a 5) also contains jS2 subunits (128). Evidence for the formation of nicotinic receptors containing four different subunits ( 4, P2, P3, and ]84) also comes from work on CNS-type subunits by Forsayeth and Kobrin (127). Finally, in autonomic neurons, another major type of nicotinic receptor is based on a7 subunits and consists of more than one pharmacological class of receptors one class resembles the recombi-... 

A. Classification Muscarinic agonists are parasympathomimetic, ie, they mimic the actions of parasympathetic nerve stimulation. Five subgroups of muscarinic receptors have been identified (Table 7-3), but selective agonists for these receptor subtypes are not available for clinical use. Nicotinic agonists are classified on the basis of whether ganglionic or neuromuscular stimulation predominates however, agonist selectivity is very limited. On the other hand, relatively selective antagonists are available for the two nicotinic receptor types (Chapter 8). 

Nicotine mimics acetylcholine at sites (a) and (b), whereas muscarine does so at site (c) (see Table 7.1). Hence it is usual to divide acetylcholine receptors into nicotinic and muscarinic receptors, a useful classification first made by Dale (1914). The work of muscarinic and nicotinic receptors is carried out on very different time scales. A single nervous stimulus affects muscarinic receptors for at least 500 ms, a long duration that is preceded by a latency of about 100 ms. In contrast to this, nicotinic receptors at voluntary neuromuscular junctions are stimulated for only 0.2 ms, and even the ganglionic synapses, which are slower, average only 60 ms. Cyclic GMP is thought to be a necessary mediator of muscarinic reponses. One consequence of interest is that smooth muscle reacts far more slowly than voluntary muscle. Heart muscle is distinguished from both by the fact that acetylcholine increases its polarization (and hence slows the heart), whereas it decreases polarization in other types of muscle. 

Figure 1 Model of cat carotid body s components thought to he involved in carotid body chemotransduction. NTS nucleus tractus solitarii in the hrainstem PG petrosal ganglion Al, A2a adenosine receptors P2X2 purinoceptor Ml, M2 types of muscarinic receptors N nicotinic receptors Dl, D2 dopamine receptors K potassium channels VGCC voltagegated calcium channels Ach acetylcholine DA dopamine NE norepinephrine SP substance P ATP adenosine triphosphate NO nitric oxide. The glomus cell, embraced by the calyx type sensory afferent fiber, contains several putative neurotransmitters. It is highly unlikely that every glomus cell contains all the listed neurotransmitters. Presumably the neurotransmitter can act wherever the appropriate receptors are located, postsynaptically as well as presynaptically. See text for postulated steps in the release of the neurotransmitters.

Fig. 1. Schematic drawing of the cholinergic neurotransmission. In case of ganglionic and neuro-muscular synapses, the receptor is of the nicotinic, sodium channel-coupled type, in case of synapses at the parasympathetic target organs, the receptor is of the muscarinic, G-protein-coupled type. The predominant ehinination pathway of the transmitter acetylcholine...

Like in the neuromuscular junction the neurotransmission can be inhibited either by receptor blockade (non-depolarizing) or by overstimulation (depolarizing) of the receptors. The alkaloid nicotine, in low doses, stimulates ganglia and the adrenaline release from the adrenal medulla. High doses lead to a continuous depolarization of the postsynaptic membrane and thereby to an inactivation of the neurotransmission. All ganglion blockers in clinical use were synthetic amines of the nondepolarizing type trimethaphan, hexamethonium and mecamylamide. 

Nicotine is highly selective for versus a, with respect to binding affinity (binding K = 1.05 r M versus 4 jM) and moderately selective with respect to functional activity (functional EC 4 [jM versus 54 jllM). Nicotine also binds with micromolaraffinity to muscle-type receptors, and affects activation in the mid to high micromolar range. Moreover, nicotine binds with micromolar affinity to ganglionic receptors and elicits functional responses in... 

The major receptor types are ganglionic nicotinic (N ), endplate nicotinic (NM), muscarinic and adrenergic receptor of four major subtypes (a,, p, P2). ACh is the neurotransmitter at all N receptors, at the M receptors innervated by postganglionic fibers of the PANS, and the thermoregulatory sweat glands innervated by the SANS. Norepinephrine (NE) is the neurotransmitter at adrenoreceptors innervated by the SANS. NE and epinephrine (E) are released from the adrenal medulla. Dopamine (DA) receptor activation leads to vasodilation in some vascular beds. 

Postsynaptic receptors, including two types of muscarinic receptors and at least one type of peptidergic receptor, have been found in ganglionic synapses, where nicotinic transmission is primary. These receptors may facilitate or inhibit transmission by evoking slow excitatory or inhibitory postsynaptic potentials (EPSPs or IPSPs). 

The cholinergic synapses in autonomic ganglia are more complex Each ganglionic cell has many synaptic inputs. The receptors on the postsynaptic membrane differ qualitatively. The ChR principally responsible for the transmission is of the nicotinic type (N-ChR). In addition, there are receptors of muscarinic type (M-ChR see p. 242). 

---