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CHAPTER 14 - Second Messengers

Terms in this set (4)

Describe the activation of G protein-coupled receptors stimulates cyclic adenosine monophosphate (cAMP) production and protein kinase A.
A.The cAMP cycle
The binding of a transmitter to certain receptors activates the stimulatory G protein (Gs), consisting of αs-, β-, and γ-subunits. When activated, the αs-subunit exchanges its bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP), causing αs to dissociate from the βγ complex. Next, αs associates with an intracellular domain of adenylyl cyclase, thereby stimulating the enzyme to produce cAMP from adenosine triphosphate (ATP). The hydrolysis of GTP to GDP and inorganic phosphate (Pi ) leads to dissociation of αs from the cyclase and its reassociation with the βγ complex. The cyclase then stops producing the second messenger. As transmitter dissociates from the receptor, the three subunits of the G protein reassociate, and the guanine nucleotide-binding site on the α-subunit is occupied by GDP

B.Activation of protein Kinase A
Four cAMP molecules bind to the two regulatory subunits of protein kinase A (PKA), liberating the two catalytic subunits, which are then free to phosphorylate specific substrate proteins on certain serine or threonine residues, thereby regulating protein function to produce a given cellular response. Two kinds of enzymes regulate this pathway. Phosphodiesterase's convert cAMP to adenosine monophosphate (which is inactive), and protein phosphatases remove phosphate groups (P) from the substrate proteins, releasing inorganic phosphate, Pi . Phosphatase activity is, in turn, decreased by the protein inhibitor-1 (not shown), when it is phosphorylated by PKA
Describe Protein Kinase C
The binding of transmitter to a receptor activates a G protein that activates phospholipase Cβ (PLCβ). This enzyme cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 is water soluble and diffuses into the cytoplasm, where it binds to the IP3 receptor-channel on the smooth endoplasmic reticulum, thereby releasing Ca2+ from internal stores. DAG remains in the membrane, where it recruits and activates protein kinase C (PKC). Membrane phospholipid is also a necessary cofactor for PKC activation. Some isoforms of PKC also require Ca2+ for activation. PKC is composed of a single protein molecule that has both a regulatory domain that binds DAG and a catalytic domain that phosphorylates proteins on serine or threonine residues. In the absence of DAG the regulatory domain inhibits the catalytic domain.
Describe Ca(2+)/calmodulin-dependent protein kinase
B. The calcium/calmodulin-dependent protein kinase is activated when Ca2+ binds to calmodulin and the calcium/ calmodulin complex then binds to a regulatory domain of the kinase. The kinase is composed of many similar subunits (only one of which is shown here), each having both regulatory and catalytic functions. The catalytic domain phosphorylates proteins on serine or threonine residues. (ATP, adenosine triphosphate; C, catalytic subunit; COOH, carboxy terminus; H2N, amino terminus; R, regulatory subunit.)
Explain the 4 steps when a short exposure to transmitter activates the cAMP second-messenger system
1) activates PKA

(2). The kinase phosphorylates a K+ channel; this leads to a synaptic potential that lasts for several minutes and modifies the excitability of the neuron

(3). With sustained activation of the receptor, the kinase translocates to the nucleus, where it phosphorylates one or more transcription factors that turn on gene expression

(4). As a result of the new protein synthesis, the synaptic actions are prolonged closure of the channel and changes in neuronal excitability last days or longer
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