the viral hemagglutinin in the presence of the drug 
led to the suggestion that is an ion channel that is 
required in virus particles to facilitate the viral un- 
coating process in secondary endosomes. To exam- 
ine directly for ion channel activity, Dr. Lamb and 
his colleagues collaborated with Dr. Lawrence Pinto 
(Northwestern University) and expressed wild-type 
M2 protein in oocytes of Xenopus laevis. The M2 
protein was shown to have an associated ion channel 
activity selective for monovalent ions, and the anti- 
viral drug amantadine hydrochloride significantly 
attenuated the inward current induced by hyperpo- 
larization of oocyte membranes. Mutations in the M2 
membrane-spanning domain that confer viral resis- 
tance to amantadine produced currents that were 
resistant to the drug. The M2 protein bears no simi- 
larity to the structure of most ion channels cloned to 
date. Thus to eliminate the possibility that M2 is a 
regulatory protein that activates a normally silent 
channel endogenous to oocytes, the currents of al- 
tered M2 proteins were measured. That these 
currents showed a particular pattern for each mu- 
tant suggests that the channel pore is formed by the 
transmembrane domain of the M2 protein, and thus 
it is a channel per se. Significantly, for the presumed 
role of the virion ion channel in virus uncoating in 
the acidic environment of secondary endosomes, 
the wild-type M2 channel was found to be regulated 
by pH. The laboratory is currently performing a de- 
tailed structure-function analysis of this unusual ion 
channel. It is also testing whether other small inte- 
gral membrane proteins encoded by viruses have a 
similar biological activity. Discrete aspects of this 
project are supported by a grant from the National 
Institute of Allergy and Infectious Diseases, National 
Institutes of Health. 
Dr. Lamb is also John Evans Professor of Molec- 
ular and Cellular Biology at Northwestern Univer- 
sity, Evanston, and Professor of Microbiology- 
Immunology at Northwestern University Medical 
School. 
Articles 
Horvath , C . M . , and Lamb, R. A. 1992. Studies on the 
fusion peptide of a paramyxovirus fusion glyco- 
protein: roles of conserved residues in cell fusion. 
/Wro/ 66:2443-2455. 
Horvath, CM., Paterson, R.G., Shaughnessy, M.A., 
Wood, R , and Lamb, R.A. 1992. Biological activ- 
ity of paramyxovirus fusion proteins: factors in- 
fluencing formation of syncytia./ Wro/ 66:4564- 
4569. 
Ng, D.T.W., Watowich, S.S., and Lamb, R.A. 1992. 
Analysis in vivo of GRP78-BiP/substrate interac- 
tions and their role in induction of the GRP78-BiP 
gene . Mol Biol Cell 3:143-155. 
Parks, G.D., Ward, CD., and Lamb, R.A. 1992. 
Molecular cloning of the NP and L genes of simian 
virus 5: identification of highly conserved do- 
mains in paramyxovirus NP and L proteins. Virus 
Res 22:259-279. 
Pinto, L.H., Holsinger, L.J., and Lamb, R.A. 1992. 
Influenza virus M2 protein has ion channel activ- 
ity. Ce// 69:517-528. 
Simpson, D.A., and Lamb, R.A. 1991. Influenza 
virus ts6\S hemagglutinin is significantly defec- 
tive in polypeptide folding and intracellular trans- 
port at the permissive temperature. Virology 
185:477-483. 
Simpson, D.A., and Lamb, R.A. 1992. Alterations to 
influenza virus hemagglutinin cytoplasmic tail 
modulate virus infectivity. / Virol 66:790-803- 
ADRENERGIC RECEPTORS 
Robert J. Lefkowitz, M.D., Investigator 
The major themes of research in this laboratory 
are the elucidation of the molecular properties and 
regulatory influences that characterize the receptor 
binding sites for catecholamines such as epineph- 
rine and norepinephrine. These receptors can be cat- 
egorized into two broad classes, a- and /3-adrenergic 
receptors, that mediate the effects of catechol- 
amines and related drugs on a wide variety of physio- 
logical processes. These adrenergic receptors are, in 
turn, prototypic of a much broader group of recep- 
tors coupled to guanine nucleotide regulatory pro- 
teins that mediate the effects of many agents on a 
remarkably diverse array of physiological functions. 
The function of G protein-coupled receptors, 
such as the |8-adrenergic receptor, is rapidly regu- 
lated by phosphorylation and dephosphorylation re- 
actions involving several distinct protein kinases. In 
addition to the cAMP-dependent protein kinase, this 
unique system involves a family of G protein- 
coupled receptor kinases and the arrestin proteins. 
86 
