Neuroscience Online

Section I: Cellular and Molecular Neurobiology 11. Acetylcholine Neurotransmission Part 5 of 8 Jack C. Waymire, Ph.D.

ACh Receptors

Table I summarizes some of the properties of nicotinic and muscarinic receptors.

The Muscarinic Receptor is Coupled to G-Proteins

ACh has excitatory actions at the neuromuscular junction, at autonomic ganglion, at certain glandular tissues and in the CNS. It has inhibitory actions at certain smooth muscles and at cardiac muscle.

Figure 11.10 Muscarinic receptors are seven transmembrane proteins that mediate their signals through G proteins.

The biochemical responses to stimulation of muscarinic receptor involve the receptor occupancy causing an altered conformation of an associated GTP-binding protein (G protein). G protein is made up of the three subunits a, b and g. In response to the altered conformation of the muscarinic receptor, the a subunit of the G protein releases bound guanosine diphosphate (GDP) and simultaneously binds guanosine triphosphate (GTP). The binding of GTP "activates" the G protein, allowing dissociation of the a subunit from the trimeric complex and for it to interact with effector systems to mediate specific responses. An inherent GTPase catalytic activity of the G protein hydrolyzes the GTP back to GDP. This hydrolysis terminates the action of the G protein. The rate of hydrolysis of the GTP thus dictates the length of time the G protein remains activated.

The responses mediated by muscarinic receptors through G proteins include:
1.	Figure 11.11 Activated G protein interacts with adenylyl cyclase to either activate or inhibit its activity. Inhibition of Adenylate Cyclase: The muscarinic receptor, through interaction with an inhibitory GTP-binding protein, acts to inhibit adenylyl cyclase. Reduced cAMP production leads to reduced activation of cAMP-dependent protein kinase, reduced heart rate, and contraction strength.
2.	Stimulation of Phospholipase C: The muscarinic receptor activates phosphoinositide-specific phospholipase C (PLCb) through interaction with a GTP-binding protein. As shown in Figure 11.12a, the hydrolysis of phosphatidylinositol bis-phosphate yields two second messengers; inositol tris-phosphate (IP3) and diacylglycerol (DAG). The DAG activates protein kinase C (not shown). Cellular responses are influenced by PKC's phosphorylation of target proteins. As shown in Figure 11.12b, the IP3 diffuses to the smooth endoplasmic reticulum (ER) where it interacts with IP3 receptors to increase Ca2+ release from the intracellular storage site. Figure 11.12a G protein stimulation of PLCb generates DAG and IP3. The DAG stimulates PKC and IP3 frees Ca2+ from smooth ER. Figure 11.12b Stimulation of IP3 receptors by four molecules stimulates the release of Ca2+ from the smooth ER.
3.	Figure 11.13 G protein directly increases K+ conductance by interacting with the K+ channels Activation of K+ Channels: In response to muscarinic cholinergic receptor stimulation, a GTP binding protein also can interact directly with K+ channels to increase K+ conductance, (Figure 11.13). This conductance increase increases the resting membrane potential in myocardial and other cell membranes leading to inhibition.