First messengers

A second messenger is an intracellular metabolite or ion whose concentration is altered when a receptor is activated by an agonist, considered to be the first messenger. ... 

Figure 11. A summary cartoon illustrating the relationships between the first messengers and the release of Ca ions from the SR, the various pathways that influence the intracellular ion concentration, and the activation of MLCK, which leads to contraction.

Metabotropic Those not directly linked to ion channels but initiating biochemical processes that mediate more long-term effects and modify the responsiveness of the neuron. With these the first messenger of synaptic transmission, the NT, activates a second messenger to effect the change in neuron excitability. They are normally associated with reduced membrance conductance and ion flux (unless secondary to... 

The neurotransmitters of the ANS and the circulating catecholamines bind to specific receptors on the cell membranes of effector tissue. Each receptor is coupled to a G protein also embedded within the plasma membrane. Receptor stimulation causes activation of the G protein and formation of an intracellular chemical, the second messenger. (The neurotransmitter molecule, which cannot enter the cell, is the first messenger.) The function of intracellular second messenger molecules is to elicit tissue-specific biochemical events within the cell that alter the cell s activity. In this way, a given neurotransmitter may stimulate the same type of receptor on two different types of tissue and cause two different responses due to the presence of different biochemical pathways within each tissue. 

Figure 10.1 ThecyclicAMPsecondmessengersystem.Themostcommonsecond messenger system activated by the protein/peptide hormones and the catecholamines involves the formation of cAMP. This multistep process is initiated by binding of the hormone (the first messenger) to its receptor on the cell surface. The subsequent increase in the formation of cAMP (the second messenger) leads to the alteration of enzyme activity within the cell. A change in the activity of these enzymes alters cellular metabolism.

Many neuropeptides were originally identified as pituitary or gastrointestinal hormones 317 Peptides can be grouped by structural and functional similarity 317 The function of peptides as first messengers is evolutionarily very old 318 Various techniques are used to identify additional neuropeptides 319 The neuropeptides exhibit a few key differences from the classical neurotransmitters 319... 

The function of peptides as first messengers is evolu-tionarily very old. In phylogenetic terms, neuropeptides were established very early as molecules effecting intercellular communication. In coelenterates, such as Hydra, there are many peptides used in neurotransmission, but many of the conventional neurotransmitter systems, such as acetylcholine (ACh), catecholamines and serotonin,... 

The details of the mechanism by which CREB influences gene expression are becoming increasingly understood (Fig. 23-9) [62, 63]. In the basal, or unstimulated, state, CREB is bound to its CREs but does not alter transcriptional rates under most circumstances. Stimulation of a cell by a variety of first messengers leads to the phosphorylation and activation of CREB, which then leads to the regulation of gene transcription. Such phosphorylation of CREB occurs on a single serine residue, serine 133, and can be mediated by one of several protein kinases. 

The detailed mechanisms involved in CREB phosphorylation were first established for the cAMP pathway. A first messenger that increases cAMP concentrations leads to activation of PKA and to translocation of the free catalytic subunit of the protein kinase into the nucleus, where it phosphorylates CREB on serine 133. Such phosphorylation then promotes the binding of CREB to a CREB-binding protein (CBP). CBP, upon binding CREB, interacts directly with the RNA polymerase II complex, which mediates the initiation of transcription. In most cases, such interactions lead to the activation of transcription, although it is possible that the expression of some genes may be repressed. 

Stimulation of a cell by first messengers that increase cellular Ca2+ concentrations similarly activates CREB (Fig. 23-9). This appears to occur via the phosphorylation of CREB on serine 133 by a CaMK, probably CaMKIV as well as, possibly, CaMKI. It remains to be established whether the activated kinase translocates to the nucleus, by analogy with the catalytic subunit of the cAMP kinase, or whether elevated Ca2+ signals enter the nucleus and activate the kinase already there. Interestingly, phosphorylation of CREB on a distinct serine residue, serine 142, by CaMKII appears to inhibit the transcriptional activity of CREB in vitro, although whether this inhibitory effect occurs in vivo is unknown. 

This can be illustrated by known interactions between the cAMP and Ca2+ pathways. A first messenger that initially activates the cAMP pathway would be expected to exert secondary effects on the Ca2+ pathway at many levels via phosphorylation by PKA. First, Ca2+ channels and the inositol trisphosphate (IP3) receptor will be phosphorylated by PKA to modulate intracellular concentrations of Ca2+. Second, phospholipase C (PLC) is a substrate for PKA, and its phosphorylation modulates intracellular calcium concentrations, via the generation of IP3) as well as the activity of PKC, via the generation of DAG, and several types of CAMK. Similarly, the Ca2+ pathway exerts potent effects on the cAMP pathway, for example, by activating or inhibiting the various forms of adenylyl cyclase expressed in mammalian tissues (see Ch. 21). 

Cells respond to their environment by taking cues from hormones or other external chemical signals. The interaction of these extracellular chemical signals ( first messengers ) with receptors on the cell surface often leads to the production of second messengers inside the cell, which in turn leads to adaptive changes in the cell interior (Chapter 12). Often, the second messenger is a nucleotide (Fig. 8-42). One of the most common is adenosine 3, 5 -cyclic monophosphate... 

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