Even if you can only answer one of the questions it would be appreciated. a) Describe the differences between the R groups of the amino acids located in the transmembrane domains and those located in the amino- or carboxy-terminus of TRPV1. Describe the specific location in the cell where TRPV1 protein is synthesized.

(b) The pGoG protein leads to the inhibition of cyclin activity. Explain how this interferes with cell cycle progression.

(c) Researchers discover a mutation that prevents NFAT2 from being phosphorylated. Predict the effect of this mutation on apoptosis by the pathway shown in Figure 2. Provide reasoning to justify your prediction.

(d) The drug cyclosporin A is known to inhibit calcineurin. Researchers claim that cyclosporin A should not be given to patients with cancer. Support the researchers' claim based on the pathway shown in Figure 2.

The perception of pain throughout the body arises when neural signals originating from the terminals of nociceptors are propagated to second-order neurons in the spinal cord or brainstem, whereupon they are transmitted to specific higher-order brain areas (Price, 2000). Recent studies have begun to elucidate some of the molecular mechanisms underlying the transduction of noxious stimuli. Many stimuli have been found to activate ion channels present on nociceptor terminals that act as molecular transducers to depolarize these neurons, thereby setting off nociceptive impulses along the pain pathways (Price, 2000; Costigan and Woolf, 2000). Among these ion channels are the members of the transient receptor potential (TRP) family. To date, the most studied member of the TRP family is the TRPV1 receptor. This is because it is the only one activated by capsaicin, the compound in chili pepper responsible for its “hot” taste; also, inhibiting TRPV1 has been shown to have therapeutic value (DiMarzo et al., 2002; Cortright and Szallasi, 2004). Although we will focus on the presence of these channels in nociceptors, we note that they have been identified in many other cell types and in various cortical and subcortical areas (Toth et al., 2005).  The transient receptor potential vanilloid 1 (TRPV1) channel is predicted to have six transmembrane domains and a short, pore-forming hydrophobic stretch between the fifth and sixth transmembrane domains (see Figure 5.1A). It is activated not only by the vanilloid capsaicin (Caterina et al., 1997), but also by noxious heat (>43°C) and low pH (Caterina et al., 1997; Tominaga et al., 1998), voltage (Gunthorpe et al., 2000; Piper et al., 1999), and various lipids (Julius and Basbaum, 2001; Caterina and Julius, 2001; Clapham, 2003; Cortright and Szallasi, 2004, Szallasi and Blumberg, 1999; Prescott and Julius, 2003; Jung et al., 2004; Bhave et al., 2003). In cells, TRPV1 is inactivated by its binding to PIP2 and is released from this block by PLC-mediated PIP2 hydrolysis (Prescott and Julius, 2003). TRPV1 is widely expressed in central nervous system (CNS) tissue and highly expressed in sensory neurons of the dorsal root ganglion [19]. This receptor also localizes to neurons that line the oral and nasal cavities [10], where it is found in a subpopulation of sensory afferent nociceptive nerve fibers [20].

(this is for question 1.)

Explanation: