on occasion by the implication made by some investigators that induction 
of c -fos mRNA or protein indicates significant phenotypic alterations in the 
/bs-ex pressing neurons. Much of this latter concern could be alleviated if 
researchers were conceptually clear as to whether they were using c-/bs as 
a marker of activation of second messenger pathways, whether they were 
investigating its biological functions within neurons, or both. 
Like all intracellular signaling molecules, the c-/bsgene product may have a 
significant biological effect depending on the state of many other molecules in 
the cell at the time of its induction. Moreover, under circumstances of normal 
stimulation, the functions of lEGs such as c-/bsare likely to be involved more 
often in homeostasis than in change (e.g., coupling new synthesis of peptides 
to secretion) (Morgan and Curran 1991). However, even mechanisms that are 
primarily homeostatic under certain circumstances may contribute to significant 
functional plasticity in the nervous system under others. For example, one 
important hypothesis in the drug abuse field is that the state of dependence 
that occurs with repetitive administration of opiates or psychostimulants reflects 
adaptive changes within target neurons that result in altered cellular and 
synaptic function. An important candidate mechanism for the adaptive changes 
underlying the cellular basis of dependence is that repetitive drug administration 
drives intracellular signaling systems, including expression of lEGs, in such a 
fashion that the overall pattern of gene expression within the target neuron is 
altered in ways that significantly alter cellular function. 
C -FOS EXPRESSION MAY BE ACTIVATED BY MULTIPLE PATHWAYS 
C -fos has been shown to be induced by a variety of stimuli relevant to signal 
transduction within the nervous system, Including growth factors (Fisch et al. 
1987; Rivera and Greenberg 1990), and multiple intracellular messenger 
pathways such as those activated by depolarization (Sheng et al. 1988, 1990) 
and calcium entry (Fisch et al. 1987; Sheng et al. 1988), the cyclic AMP 
(cAMP)/protein kinase A pathway (Sassone-Corsi et al. 1988; Fisch et al. 
1989), the protein kinase C pathway (Fisch et al. 1987; Gilman 1988), and 
others. C -fos expression appears to be blocked by agents that facilitate the 
hyperpolarization of neurons (Morgan et al. 1987). Since the stimulation of 
many neurotransmitter receptor types within the nervous system leads to 
activation of calcium-dependent protein kinases, protein kinase A, or one or 
more isoforms of protein kinase C, it is not surprising that many neural stimuli 
or drugs that affect excitatory or G protein-linked synaptic transmission also 
activate c-fos. Moreover, the activation of more than one of these pathways 
may produce synergistic activation of gene expression (Sheng et al. 1990). 
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