Question

The chemical Bay K8644 is an activator of voltage-gated Ca²⁺ channels.   If you were to inject this chemical into a frog, how would you predict neuron function would be affected? Make sure you describe how an action potential reaching the synapse results in a response in the post-synaptic cell (i.e. what are the steps involved in chemical synapse function)?

Answer 1

Neurons communicate with each other via signaling at the synapse. This signaling is via generation of action potential. The pre-synaptic neuron will generate an action potential in response to signals received which then causes the release of neurotransmitter (chemical signal) from presynaptic vesicles at the axon terminal. Neurotransmitter is released at the synapse. This neurotransmitter can be inhibitory or excitatory neurotransmitter, depending on whether the action potential is stimulated or inhibited in the post-synaptic neuron.

At the synapse, the neurotransmitter will bind to the receptor present on the plasma membrane of the post-synaptic neuron. Depending on the neurotransmitter, voltage gated ion channels associated with the receptor are opened. Positive ions include Na+,Ca2+ etc are excitatory and will cause generation of action potential in post-synaptic membrane. Inhibitory actions are mostly via negative ions such as Cl-. Entry of positive ions will cause depolarization, which makes the membrane potential more positive. When the depolarization increases beyond a threshold potential, an action potential is generated. Once action potential is generated, the membrane potential becomes more negative via repolarization. The resting membrane potential is reinstated via hyperpolarization.

DRG neurons of frog are sensory neurons that are activated by sensory stimuli. The effect of Bay 8644 on the L type calcium channels lead to increased currents. L type calcium channels are required for calcium release. The increased calcium will cause the presynaptic vesicles that contain neurotransmitter to fuse with the presynaptic neuron. As a result, there will be increased release of neurotransmitter at the synapse. Dopamine is the neurotransmitter that is released by DRG neurons. Dopamine can be inhibitory or stimulator depending on its role. Its secretion will increase when the frog are treated with Bay 8644. Similar actions will be seen on all neurons that contain the L type Ca channels. This leads to increase neurotransmitter release by the pre-synaptic neurons.

In skeletal muscles of the frog, there are L type calcium channels called dihydropyridine receptor (DHPR) that are coupled to ryanodine receptor/Ca2+ release channel (RyR/CRC). Skeletal muscle acts as post synaptic cell of the neuromuscular junction. Increased binding of neurotransmitter to the receptor lead to opening of L type calcium channel which leads to increased calcium conductance. Increased calcium conductance will cause the RyR to be stimulated. This will lead to increased calcium release from the sarcoplasmic reticulum. As a result, calcium will bind to troponin and will free myosin binding sites on actin. This leads to increased cross bridging and increased muscle contraction. Bay K8644 is an activator of L type voltage gated calcium channels. Bay K8644 does not affect the channel conductance but maintain large stable opening of the channel. Hence, Bay K8644 increased muscle contraction. Thus, there will be tetanic contractions in the frog skeletal muscles.

In case of cardiac muscles, the opening of the L type calcium channels in the cardiac cells will lead to increased contraction. Thus, there will be increased contractile force in heart. In case of vascular smooth muscle, increase ICa generated will lead to blood vessel constriction due to increased release of calcium. Calcium is known to increase activity of myosin light chain kinase that phosphorylates myosin for increased contraction.

Thus, neurons will be stimulated for increased neurotransmitter release when the frog is treated with Bay 8644.